U.S. patent number 8,580,796 [Application Number 13/350,117] was granted by the patent office on 2013-11-12 for low hygroscopic aripiprazole drug substance and processes for the preparation thereof.
This patent grant is currently assigned to Otsuka Pharmaceutical Co., Ltd.. The grantee listed for this patent is Kaoru Abe, Satoshi Aoki, Takuji Bando, Kiyoshi Fujimoto, Tsutomu Fujimura, Makoto Ishigami, Junichi Kawasaki, Noriyuki Kobayashi, Tomonori Nakagawa, Yoshihiro Nishioka, Yoshihiro Ooi, Koichi Shinhama, Masanori Takahashi, Youichi Taniguchi, Kenji Tomikawa, Michiaki Tominaga, Naoto Utsumi, Tsuyoshi Yabuuchi, Shohei Yamada. Invention is credited to Kaoru Abe, Satoshi Aoki, Takuji Bando, Kiyoshi Fujimoto, Tsutomu Fujimura, Makoto Ishigami, Junichi Kawasaki, Noriyuki Kobayashi, Tomonori Nakagawa, Yoshihiro Nishioka, Yoshihiro Ooi, Koichi Shinhama, Masanori Takahashi, Youichi Taniguchi, Kenji Tomikawa, Michiaki Tominaga, Naoto Utsumi, Tsuyoshi Yabuuchi, Shohei Yamada.
United States Patent |
8,580,796 |
Bando , et al. |
November 12, 2013 |
**Please see images for:
( Certificate of Correction ) ** |
Low hygroscopic aripiprazole drug substance and processes for the
preparation thereof
Abstract
The present invention provides low hygroscopic forms of
aripiprazole and processes for the preparation thereof which will
not convert to a hydrate or lose their original solubility even
when a medicinal preparation containing the anhydrous Aripiprazole
crystals is stored for an extended period.
Inventors: |
Bando; Takuji (Tokushima,
JP), Aoki; Satoshi (Naruto, JP), Kawasaki;
Junichi (Tokushima, JP), Ishigami; Makoto
(Tokushima, JP), Taniguchi; Youichi (Tokushima,
JP), Yabuuchi; Tsuyoshi (Tokushima, JP),
Fujimoto; Kiyoshi (Naruto, JP), Nishioka;
Yoshihiro (Tokushima, JP), Kobayashi; Noriyuki
(Tokushima, JP), Fujimura; Tsutomu (Naruto,
JP), Takahashi; Masanori (Tokushima, JP),
Abe; Kaoru (Tokushima, JP), Nakagawa; Tomonori
(Tokushima, JP), Shinhama; Koichi (Tokushima,
JP), Utsumi; Naoto (Naruto, JP), Tominaga;
Michiaki (Tokushima, JP), Ooi; Yoshihiro
(Tokushima, JP), Yamada; Shohei (Tokushima,
JP), Tomikawa; Kenji (Tokushima, JP) |
Applicant: |
Name |
City |
State |
Country |
Type |
Bando; Takuji
Aoki; Satoshi
Kawasaki; Junichi
Ishigami; Makoto
Taniguchi; Youichi
Yabuuchi; Tsuyoshi
Fujimoto; Kiyoshi
Nishioka; Yoshihiro
Kobayashi; Noriyuki
Fujimura; Tsutomu
Takahashi; Masanori
Abe; Kaoru
Nakagawa; Tomonori
Shinhama; Koichi
Utsumi; Naoto
Tominaga; Michiaki
Ooi; Yoshihiro
Yamada; Shohei
Tomikawa; Kenji |
Tokushima
Naruto
Tokushima
Tokushima
Tokushima
Tokushima
Naruto
Tokushima
Tokushima
Naruto
Tokushima
Tokushima
Tokushima
Tokushima
Naruto
Tokushima
Tokushima
Tokushima
Tokushima |
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A |
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP
JP |
|
|
Assignee: |
Otsuka Pharmaceutical Co., Ltd.
(Tokyo, JP)
|
Family
ID: |
27171631 |
Appl.
No.: |
13/350,117 |
Filed: |
January 13, 2012 |
Prior Publication Data
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|
|
Document
Identifier |
Publication Date |
|
US 20120315302 A1 |
Dec 13, 2012 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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10333244 |
|
|
|
|
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PCT/JP02/09858 |
Sep 25, 2002 |
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Current U.S.
Class: |
514/253.07;
544/363 |
Current CPC
Class: |
A61P
25/28 (20180101); A61P 25/20 (20180101); C07D
215/22 (20130101); A61P 25/00 (20180101); A61P
25/16 (20180101); A61P 25/32 (20180101); A61P
15/10 (20180101); A61P 25/06 (20180101); A61P
25/22 (20180101); A61P 25/04 (20180101); A61P
1/08 (20180101); A61P 25/24 (20180101); A61P
3/04 (20180101); C07D 215/227 (20130101); A61P
15/00 (20180101); A61P 25/18 (20180101); A61P
25/30 (20180101); Y10T 428/2982 (20150115); C07B
2200/13 (20130101) |
Current International
Class: |
A61K
31/497 (20060101); C07D 401/06 (20060101) |
Field of
Search: |
;514/253.07
;544/363 |
References Cited
[Referenced By]
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2002226752 |
|
Aug 2002 |
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AU |
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29 12 105 |
|
Aug 1985 |
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DE |
|
29 12 105 |
|
Aug 1985 |
|
DE |
|
0 226 441 |
|
Jun 1987 |
|
EP |
|
0 360 077 |
|
Mar 1990 |
|
EP |
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0 367 141 |
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May 1990 |
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EP |
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0 565 274 |
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Oct 1993 |
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EP |
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0 776 927 |
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Jun 1997 |
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EP |
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2 223 702 |
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Sep 2010 |
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EP |
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54-130587 |
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Oct 1979 |
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JP |
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56-46812 |
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Apr 1981 |
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JP |
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2-191256 |
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Jul 1990 |
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JP |
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A-70135 |
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Mar 1995 |
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JP |
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9-40648 |
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Feb 1997 |
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JP |
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11-508280 |
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Oct 1997 |
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JP |
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9-291034 |
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Nov 1997 |
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JP |
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9-301867 |
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Nov 1997 |
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JP |
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11-509865 |
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Nov 1997 |
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JP |
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11-335286 |
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Dec 1999 |
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JP |
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WO 92/10200 |
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Jun 1992 |
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WO |
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WO 92/20655 |
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Nov 1992 |
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WO |
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WO 93/04681 |
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Mar 1993 |
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WO |
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WO 94/09765 |
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May 1994 |
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WO |
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WO 94/13620 |
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Jun 1994 |
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WO |
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WO 98/07426 |
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Feb 1998 |
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WO |
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WO 98/08817 |
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Mar 1998 |
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WO |
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Aug 1999 |
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WO |
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Oct 1999 |
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WO |
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Aug 2002 |
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WO |
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WO 02/102297 |
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Dec 2002 |
|
WO |
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WO 03/026659 |
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Apr 2003 |
|
WO |
|
WO 03/030868 |
|
Apr 2003 |
|
WO |
|
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|
Primary Examiner: Wilson; James O
Assistant Examiner: Sackey; Ebenezer O
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner LLP
Parent Case Text
RELATED APPLICATIONS
This application is a continuation of application Ser. No.
10/333,244, which is a .sctn.371 of International Application No.
PCT/JP02/09858, filed Sep. 25, 2002, which claims priority of
Japanese Application Nos. JP 2001-290645, filed Sep. 25, 2001, and
JP 2001-348276, filed Nov. 14, 2001, and of Canadian Application
No. CA 2379005, filed Mar. 27, 2002, the contents of all of which
are incorporated by reference.
Claims
The invention claimed is:
1. Anhydrous Aripiprazole Crystals B having low hygroscopicity
wherein said low hygroscopicity is defined as a moisture content of
0.40% or less when said Crystals are placed for 24 hours in a
dessicator maintained at a temperature of 60.degree. C. and a
humidity level of 100%.
2. Anhydrous Aripiprazole Crystals B having low hygroscopicity
wherein said low hygroscopicity is defined as a moisture content of
0.10% or less when said Crystals are placed for 24 hours in a
dessicator maintained at a temperature of 60.degree. C. and a
humidity level of 100%.
Description
DETAILED DESCRIPTION OF THE INVENTION
1. Field of the Invention
The present invention relates to an improved form of aripiprazole
having reduced hygroscopicity and processes for the preparation of
this improved form.
2. Background of the Invention
Aripiprazole,
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro
carbostyril or
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]-butoxy}-3,4-dihydro-2(1H)-qui-
nolinone, is an atypical antipsychotic agent useful for the
treatment of schizophrenia (U.S. Pat. No. 4,734,416 and U.S. Pat.
No. 5,006,528). Schizophrenia is a common type of psychosis
characterized by delusions, hallucinations and extensive withdrawal
from others. Onset of schizophrenia typically occurs between the
age of 16 and 25 and affects 1 in 100 individuals worldwide. It is
more prevalent than Alzheimer's disease, multiple sclerosis,
insulin-dependent diabetes and muscular dystrophy. Early diagnosis
and treatment can lead to significantly improved recovery and
outcome. Moreover, early therapeutic intervention can avert costly
hospitalization.
According to Example 1 of Japanese Unexamined Patent Publication
No. 191256/1990, anhydrous aripiprazole crystals are manufactured
for example by reacting 7-(4-bromobutoxy)-3,4-dihydrocarbostyril
with 1-(2,3-dichlorophenylpiperadine and recrystallizing the
resulting raw anhydrous aripiprazole with ethanol. Also, according
to the Proceedings of the 4th Japanese-Korean Symposium on
Separation Technology (Oct. 6-8, 1996), anhydrous aripiprazole
crystals are manufactured by heating aripiprazole hydrate at
80.degree. C. However, the anhydrous aripiprazole crystals obtained
by the aforementioned methods have the disadvantage of being
significantly hygroscopic.
The hygroscopicity of these crystals makes them difficult to handle
since costly and burdensome measures must be taken in order ensure
they are not exposed to moisture during process and formulation.
Exposed to moisture, the anhydrous form can take on water and
convert to a hydrous form. This presents several disadvantages.
First, the hydrous forms of aripiprazole have the disadvantage of
being less bioavailable and less dissoluble than the anhydrous
forms of aripiprazole. Second, the variation in the amount of
hydrous versus anhydrous aripiprazole drug substance from batch to
batch could fail to meet specifications set by drug regulatory
agencies. Third, the milling may cause the drug substance,
Conventional Anhydrous Aripiprazole, to adhere to manufacturing
equipment which may further result in processing delay, increased
operator involvement, increased cost, increased maintenance and
lower production yield. Fourth, in addition to problems caused by
introduction of moisture during the processing of these hygroscopic
crystals, the potential for absorbance of moisture during storage
and handling would adversely affect the dissolubility of
aripiprazole drug substance. Thus shelf-life of the product could
be significantly decreased and/or packaging costs could be
significantly increased. It would be highly desirable to discover a
form of aripiprazole that possessed low hygroscopicity thereby
facilitating pharmaceutical processing and formulation operations
required for producing dosage units of an aripiprazole medicinal
product having improved shelf-life, suitable dissolubility and
suitable bioavailability.
Also, Proceedings of the 4th Japanese-Korean Symposium on
Separation Technology (Oct. 6-8, 1996) state that, anhydrous
aripiprazole crystals exist as type-I crystals and type-II
crystals; the type-I crystals of anhydrous aripiprazole can be
prepared by recrystallizing from an ethanol solution of
aripiprazole, or by heating aripiprazole hydrate at 80.degree. C.;
and the type-II crystals of anhydrous aripiprazole can be prepared
by heating the type-I crystals of anhydrous aripiprazole at 130 to
140.degree. C. for 15 hours.
By the aforementioned methods, anhydrous aripiprazole type-II
crystals having high purity can not be easily prepared in an
industrial scale with good repeatability.
SUMMARY OF THE INVENTION
Thus according to the present invention is provided a form of
aripiprazole having reduced hygroscopicity and which is more
amenable to pharmaceutical processing and formulation. The
inventors of the present invention have discovered that this
reduced-hygroscopic form of Aripiprazole is a crystalline substance
defined herein as Anhydrous Aripiprazole Crystals B. A particular
process for the preparation of this anhydrous crystalline substance
has also been discovered and comprises yet another aspect of the
present invention. Particularly, it was discovered as part of the
present invention that in order to produce Anhydrous Aripiprazole
Crystals B having the desired pharmaceutical properties and
utilizing the most efficient process, Hydrate A, as defined herein,
would have to serve as the intermediate. It was also discovered
that a particular sequence of processing had to be implemented in
order to form Hydrate A. It was discovered that the preparation of
Hydrate A required milling what is defined herein as Conventional
Hydrate. Then, Hydrate A can be transformed into Anhydrous
Aripiprazole Crystals B through suitable heating as defined herein.
Surprisingly, if the Conventional Hydrate is first heated and then
milled, serious agglomeration sets in rendering the processing
commercially unsuitable.
An object of the present invention is to provide novel anhydrous
aripiprazole crystals.
Moreover, another object of the present invention is to provide
anhydrous aripiprazole crystals which neither easily convert into
hydrates nor substantially decrease the original solubility, even
when a pharmaceutical composition comprising anhydrous aripiprazole
is stored for a long period of time.
Further object of the present invention is to provide preparation
methods, in order to obtain anhydrous aripiprazole crystals having
high purity in an industrial scale with good repeatability.
The present inventors have conducted research works aimed to attain
the aforementioned objects. In the course of the research, they
have found that the desired anhydrous aripiprazole crystals can be
obtained when a well-known anhydrous aripiprazole is heated at the
specific temperature. Further, the present inventors have found
that the desired anhydrous aripiprazole crystals can be obtained
from recrystallization of a well-known anhydrous aripiprazole by
using the specific solvents. Moreover, the present inventors found
that the desired anhydrous aripiprazole crystals can be obtained by
suspending a well-known anhydrous aripiprazole in the specific
solvent, and heating thus obtained suspension.
The present invention thus completed on the basis of these findings
and knowledge.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a thermogravimetric/differential thermogram of the
Aripiprazole Hydrate A obtained in Example 1.
FIG. 2 shows the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of the
Aripiprazole Hydrate A obtained in Example 1.
FIG. 3 is a powder x-ray diffraction diagram of the Aripiprazole
Hydrate A obtained in Example 1.
FIG. 4 shows the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of the
Anhydrous Aripiprazole Crystals B obtained in Example 2.
FIG. 5 is a powder x-ray diffraction diagram of the Anhydrous
Aripiprazole Crystals B obtained in Example 2.
FIG. 6 is a thermogravimetric/differential thermogram of the
aripiprazole hydrate obtained in Reference Example 3.
FIG. 7 is a powder x-ray diffraction diagram of the aripiprazole
hydrate obtained in Reference Example 3.
FIG. 8 shows thermogravimetric/differential thermal analysis
endothermic curve of the type C crystals of anhydrous aripiprazole
obtained in Example 11.
FIG. 9 shows an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of the
type C crystals of anhydrous aripiprazole obtained in Example
11.
FIG. 10 shows a powder X-ray diffraction spectrum of the type C
crystals of anhydrous aripiprazole obtained in Example 11.
FIG. 11 shows an IR spectrum of the type C crystals of anhydrous
aripiprazole obtained in Example 11.
FIG. 12 shows a solid .sup.13C-NMR spectrum of the type C crystals
of anhydrous aripiprazole obtained in Example 11.
FIG. 13 shows a thermogravimetric/differential thermal analysis
endothermic curve of the type D crystals of anhydrous aripiprazole
obtained in Example 12 or Example 13.
FIG. 14 shows an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of the
type D crystals of anhydrous aripiprazole obtained in Example 12 or
Example 13.
FIG. 15 shows a powder X-ray diffraction spectrum of the type D
crystals of anhydrous aripiprazole obtained in Example 12 or
Example 13.
FIG. 16 shows an IR spectrum of the type D crystals of anhydrous
aripiprazole obtained in Example 12 or Example 13.
FIG. 17 shows a solid .sup.13C-NMR spectrum of the type D crystals
of anhydrous aripiprazole obtained in Example 12 or Example 13.
FIG. 18 shows a thermogravimetric/differential thermal analysis
endothermic curve of the type E crystals of anhydrous aripiprazole
obtained in Example 14.
FIG. 19 shows an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of the
type E crystals of anhydrous aripiprazole obtained in Example
14.
FIG. 20 shows a powder X-ray diffraction spectrum of the type E
crystals of anhydrous aripiprazole obtained in Example 14.
FIG. 21 shows an IR spectrum of the type E crystals of anhydrous
aripiprazole obtained in Example 14.
FIG. 22 shows a thermogravimetric/differential thermal analysis
endothermic curve of the type F crystals of anhydrous aripiprazole
obtained in Example 15.
FIG. 23 shows an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of the
type F crystals of anhydrous aripiprazole obtained in Example
15.
FIG. 24 shows a powder X-ray diffraction spectrum of the type F
crystals of anhydrous aripiprazole obtained in Example 15.
FIG. 25 shows an IR spectrum of the type F crystals of anhydrous
aripiprazole obtained in Example 15.
FIG. 26 shows thermogravimetric/differential thermal analysis
endothermic curve of the type G crystals of anhydrous aripiprazole
obtained in Example 16-b).
FIG. 27 shows an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) of the
type G crystals of anhydrous aripiprazole obtained in Example
16-b).
FIG. 28 shows a powder X-ray diffraction spectrum of the type G
crystals of anhydrous aripiprazole obtained in Example 16-b).
FIG. 29 shows an IR spectrum of the type G crystals of anhydrous
aripiprazole obtained in Example 16-b).
FIG. 30 shows a thermogravimetric/differential thermal analysis
endothermic curve of the glass form of anhydrous aripiprazole
obtained in Example 16-a).
FIG. 31 shows a powder X-ray diffraction spectrum of the glassy
state of anhydrous aripiprazole obtained in Example 16-a).
DETAILED DESCRIPTION OF THE INVENTION
According to first embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has a powder x-ray diffraction spectrum which is
substantially the same as the powder x-ray diffraction spectrum
shown in FIG. 3.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has powder x-ray diffraction characteristic peaks at
2.theta.=12.6.degree., 15.4.degree., 17.3.degree., 18.0.degree.,
18.6.degree., 22.5.degree. and 24.8.degree..
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has particular infrared absorption bands at 2951, 2822,
1692, 1577, 1447, 1378, 1187, 963 and 784 cm.sup.-1 on the IR (KBr)
spectrum.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has an .sup.1H-NMR spectrum which is substantially the same
as the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG.
2.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) having
characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m,
2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm
(t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3
Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4
Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H),
7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has an endothermic curve which is substantially the same as
the thermogravimetric/differential thermal analysis (heating rate
5.degree. C./min) endothermic curve shown in FIG. 1.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has a mean particle size of 50 .mu.m or less.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has a mean particle size of 40 .mu.m or less.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has a mean particle size of 35 .mu.m or less.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has a mean particle size of 30 .mu.m or less.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has a mean particle size of 25 .mu.m or less.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has a mean particle size of 20 .mu.m or less.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has a mean particle size range of 40 to 10 .mu.m.
According to another embodiment of the first aspect of the present
invention is provided Hydrate A of aripiprazole wherein said
Hydrate has a mean particle size range of 36 to 14 .mu.m.
According to a second aspect of the present invention is provided a
process for the preparation of Hydrate A wherein said process
comprises the steps of milling Conventional Hydrate.
According to a first embodiment of the second aspect of the present
invention is provided a process for the preparation of Hydrate A
comprising the steps of milling Conventional Hydrate wherein said
milling is performed by a milling machine.
According to another embodiment of the second aspect of the present
invention is provided a process for the preparation of Hydrate A
comprising the steps of milling Conventional Hydrate wherein said
milling machine is an atomizer, pin mill, jet mill or ball
mill.
According to another embodiment of the second aspect of the present
invention is provided a process for the preparation of Hydrate A
comprising the steps of milling Conventional Hydrate wherein said
milling machine is an atomizer.
According to another embodiment of the second aspect of the present
invention is provided a process for the preparation of Hydrate A
comprising the steps of milling Conventional Hydrate wherein said
milling machine is an atomizer using a rotational speed of
5000-15000 rpm for the main axis, a feed rotation of 10-30 rpm and
a screen hole size of 1-5 mm.
According to various embodiments of a third aspect of the present
invention is provided Hydrate A defined according to one or more of
the embodiments described herein wherein said Hydrate is made by a
process as described herein.
According to a fourth aspect of the present invention is provided
aripiprazole drug substance of low hygroscopicity.
According to a first embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said low hygroscopicity is a moisture
content of 0.5% or less after placing said drug substance for 24
hours in a dessicator maintained at a temperature of 60.degree. C.
and a humidity level of 100%.
According to a first embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said low hygroscopicity is a moisture
content of 0.4% or less after placing said drug substance for 24
hours in a dessicator maintained at a temperature of 60.degree. C.
and a humidity level of 100%.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said low hygroscopicity is a moisture
content of 0.25% or less after placing said drug substance for 24
hours in a dessicator maintained at a temperature of 60.degree. C.
and a humidity level of 100%.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said low hygroscopicity is a moisture
content of 0.15% or less after placing said drug substance for 24
hours in a dessicator maintained at a temperature of 60.degree. C.
and a humidity level of 100%.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said low hygroscopicity is a moisture
content of 0.10% or less after placing said drug substance for 24
hours in a dessicator maintained at a temperature of 60.degree. C.
and a humidity level of 100%.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said low hygroscopicity is a moisture
content of 0.05% or less after placing said drug substance for 24
hours in a dessicator maintained at a temperature of 60.degree. C.
and a humidity level of 100%.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said low hygroscopicity is a moisture
content of 0.04% or less after placing said drug substance for 24
hours in a dessicator maintained at a temperature of 60.degree. C.
and a humidity level of 100%.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance is Anhydrous
Aripiprazole Crystals B as defined herein.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance has a powder x-ray
diffraction spectrum which is substantially the same as the powder
x-ray diffraction spectrum shown in FIG. 5.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance has a powder x-ray
diffraction spectrum having characteristic peaks at
2.theta.=11.0.degree., 16.6.degree., 19.3.degree., 20.3.degree. and
22.1.degree..
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance has particular infrared
absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960
and 779 cm.sup.-1 on the IR (KBr) spectrum.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance has an .sup.1H-NMR
spectrum which is substantially the same as the .sup.1H-NMR
spectrum (DMSO-d.sub.6, TMS) shown in FIG. 4.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance has an .sup.1H-NMR
spectrum (DMSO-d.sub.6, TMS) having characteristic peaks at
1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m,
4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97
ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d,
J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d,
J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and
10.00 ppm (s, 1H).
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance exhibits an endothermic
peak near about 141.5.degree. C. in thermogravimetric/differential
thermal analysis (heating rate 5.degree. C./min).
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance exhibits an endothermic
peak near about 140.7.degree. C. in differential scanning
calorimetry (heating rate 5.degree. C./min).
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance is Anhydrous
Aripiprazole Crystals B and will not substantially convert to a
hydrous form of aripiprazole when properly stored even for an
extended period. For instance, said Anhydrous Aripiprazole Crystals
B can be stored under a relative humidity (RH) of 60% and at a
temperature of 25.degree. C., even for a period not less than 1
year.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance is Anhydrous
Aripiprazole Crystals B and will not substantially convert to a
hydrous form of aripiprazole when properly stored even for an
extended period. For instance, said Anhydrous Aripiprazole Crystals
B can be stored under a relative humidity (RH) of 60% and at a
temperature of 25.degree. C., even for a period not less than 4
years.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance is Anhydrous
Aripiprazole Crystals B and will not substantially convert to a
hydrous form of aripiprazole when properly stored even for a period
not less than 0.5 year under a relative humidity (RH) of 75% and at
a temperature of 40.degree. C.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance has a mean size of 50
.mu.m or less when small particle size is required for the
formulation such as Tablet and other solid dose formulations
including for example flashmelt formulations.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance has a mean size of 40
.mu.m or less if small particle size is required for the
formulation such as Tablet and other solid dose formulations
including for example flashmelt formulations.
According to another embodiment of the fourth aspect of the present
invention is provided aripiprazole drug substance of low
hygroscopicity wherein said drug substance has a mean size of 30
.mu.m or less if small particle size is required for formulation
such as Tablet and other solid dose formulations including for
example flashmelt formulations.
According to a fifth aspect of the present invention is provided a
process for the preparation of Anhydrous Aripiprazole Crystals
B.
According to a first embodiment of the fifth aspect of the present
invention is provided a process for the preparation of Anhydrous
Aripiprazole Crystals B wherein said process comprises heating
Aripiprazole Hydrate A.
According to a first embodiment of the fifth aspect of the present
invention is provided a process for the preparation of Anhydrous
Aripiprazole Crystals B wherein said process comprises heating
Aripiprazole Hydrate A at 90-125.degree. C. for about 3-50
hours.
According to another embodiment of the fifth aspect of the present
invention is provided a process for the preparation of Anhydrous
Aripiprazole Crystals B wherein said process comprises heating
Aripiprazole Hydrate A at 100.degree. C. for about 18 hours.
According to another embodiment of the fifth aspect of the present
invention is provided a process for the preparation of Anhydrous
Aripiprazole Crystals B wherein said process comprises heating
Aripiprazole Hydrate A at 100.degree. C. for about 24 hours.
According to another embodiment of the fifth aspect of the present
invention is provided a process for the preparation of Anhydrous
Aripiprazole Crystals B wherein said process comprises heating
Aripiprazole Hydrate A at 120.degree. C. for about 3 hours.
According to another embodiment of the fifth aspect of the present
invention is provided a process for the preparation of Anhydrous
Aripiprazole Crystals B wherein said process comprises heating
Aripiprazole Hydrate A for about 18 hours at 100.degree. C.
followed by additional heating for about 3 hours at 120.degree.
C.
According to a sixth aspect of the present invention is provided
Anhydrous Aripiprazole Crystals B defined according to one or more
of the embodiments described herein and made by a process as
provided herein.
According to a seventh aspect of the present invention is provided
Anhydrous Aripiprazole Crystals B formulated with one or more
pharmaceutically acceptable carriers.
Other embodiments of the present invention may comprise suitable
combinations of two or more of the embodiments and/or aspects
disclosed herein.
Yet other embodiments and aspects of the invention will be apparent
according to the description provided below.
Yet another aspect of the present invention comprised discovering
that when aripiprazole hydrate (Conventional Hydrate as defined
herein) is milled, it converts to an aripiprazole hydrate (Hydrate
A as defined herein) with a different powder x-ray diffraction
spectrum by different peak intensities. Moreover, it was found that
Hydrate A loses the sharp dehydration endothermic peak of
123.5.degree. C. which characterizes unmilled Conventional Hydrate
in thermogravimetric/differential thermal analysis. Thus, the
Conventional Hydrate is transformed into Hydrate A after milling
Conventional Hydrate and exhibits a gradual dehydration endothermic
peak between about 60.degree. C. and 120.degree. C. with a weak
peak at about 71.degree. C.
Yet another aspect of the invention comprised discovering that when
heated to a specific temperature of 90-125.degree. C. for 3-50 hr,
this novel aripiprazole hydrate dehydrates gradually avoiding the
aggregation phenomenon thought to be caused in conventional
aripiprazole hydrate by rapid dehydration, and that anhydrous
aripiprazole crystals obtained by heating of the novel aripiprazole
hydrate to a specific temperature are anhydrous aripiprazole
crystals with the desired properties.
Characterization of Hydrate A
Particles of "Hydrate A" as used herein have the physicochemical
properties given in (1)-(5) below:
(1) It has an endothermic curve which is substantially the same as
the thermogravimetric/differential thermal analysis (heating rate
5.degree. C./min) endothermic curve shown in FIG. 1. Specifically,
it is characterized by the appearance of a small peak at about
71.degree. C. and a gradual endothermic peak around 60.degree. C.
to 120.degree. C.
(2) It has an .sup.1H-NMR spectrum which is substantially the same
as the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 2.
Specifically, it has characteristic peaks at 1.55-1.63 ppm (m, 2H),
1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,
4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H),
3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm
(dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17
ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).
(3) It has a powder x-ray diffraction spectrum which is
substantially the same as the powder x-ray diffraction spectrum
shown in FIG. 3. Specifically, it has characteristic peaks at
2.theta.=12.6.degree., 15.4.degree., 17.3.degree., 18.0.degree.,
18.6.degree., 22.5.degree. and 24.8.degree..
(4) It has clear infrared absorption bands at 2951, 2822, 1692,
1577, 1447, 1378, 1187, 963 and 784 cm.sup.-1 on the IR (KBr)
spectrum.
(5) It has a mean particle size of 50 .mu.m or less.
Process for Manufacturing Hydrate A
Hydrate A is manufactured by milling Conventional Hydrate.
Conventional milling methods can be used to mill Conventional
Hydrate. For example, Conventional Hydrate can be milled in a
milling machine. A widely used milling machine can be used, such as
an atomizer, pin mill, jet mill or ball mill. Of these, the
atomizer is preferred.
Regarding the specific milling conditions when using an atomizer, a
rotational speed of 5000-15000 rpm could be used for the main axis,
for example, with a feed rotation of 10-30 rpm and a screen hole
size of 1-5 mm.
The mean particle size of the Aripiprazole Hydrate A obtained by
milling should normally be 50 .mu.m or less, preferably 30 .mu.m or
less. Mean particle size can be ascertained by the particle size
measurement method described hereinafter.
Characterization of Anhydrous Aripiprazole Crystals B
"Anhydrous Aripiprazole Crystals B" of the present invention as
used herein have the physicochemical properties given in (6)-(12)
below.
(6) They have an .sup.1H-NMR spectrum which is substantially the
same as the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG.
4. Specifically, they have characteristic peaks at 1.55-1.63 ppm
(m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56
ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6
Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H),
6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),
7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s,
1H).
(7) They have a powder x-ray diffraction spectrum which is
substantially the same as the powder x-ray diffraction spectrum
shown in FIG. 5. Specifically, they have characteristic peaks at
2.theta.=11.0.degree., 16.6.degree., 19.3.degree., 20.3.degree. and
22.1.degree..
(8) They have clear infrared absorption bands at 2945, 2812, 1678,
1627, 1448, 1377, 1173, 960 and 779 cm.sup.-1 on the IR (KBr)
spectrum.
(9) They exhibit an endothermic peak near about 141.5.degree. C. in
thermogravimetric/differential thermal analysis (heating rate
5.degree. C./min).
(10) They exhibit an endothermic peak near about 140.7.degree. C.
in differential scanning calorimetry (heating rate 5.degree.
C./min).
(11) Anhydrous Aripiprazole Crystals B of the present invention
have low hygroscopicity. For example, Anhydrous Aripiprazole
Crystals B of the present invention maintain a water content of
0.4% or less after 24 hours inside a dessicator set at a
temperature of 60.degree. C. and a humidity of 100%. Well-known
methods of measuring water content can be used as long as they are
methods commonly used for measuring the water content of crystals.
For example, a method such as the Karl Fischer method can be
used.
(12) When the small particle size is required for the formulation
such as tablet and other solid dose formulations including for
example flashmelt formulations, the mean particle size is
preferably 50 .mu.m or less.
Process for Manufacturing Anhydrous Aripiprazole Crystals B
In case of the formulation for which small particle size (less than
50 .mu.m) is required, the milling is necessary for the
preparation. However, when a large amount of Conventional Anhydrous
Aripiprazole or Anhydrous Aripiprazole Crystals B having large
particle size is milled, the milled substances adhere with each
other in the milling machine. Accordingly, there is a disadvantage
that it is difficult to industrially prepare Anhydrous Aripiprazole
Crystals B having small particle size.
Under the circumstances, the inventors of the present invention
have found that Conventional hydrate can be easily milled, and
Anhydrous Aripiprazole Crystals B having small particle size can be
obtained in high yield with good-operability by heating the milled
hydrate A thus obtained.
The Anhydrous Aripiprazole Crystals B of the present invention are
prepared for example by heating the aforementioned Aripiprazole
Hydrate A at 90-125.degree. C. The heating time is generally about
3-50 hours, but cannot be stated unconditionally since it differs
depending on heating temperature. The heating time and heating
temperature are inversely related, so that for example the heating
time will be longer the lower the heating temperature, and shorter
the higher the heating temperature. Specifically, if the heating
temperature of Aripiprazole Hydrate A is 100.degree. C., the
heating time should normally be 18 hours or more or preferably
about 24 hours. If the heating temperature of Aripiprazole Hydrate
A is 120.degree. C., on the other hand, the heating time can be
about 3 hours. The Anhydrous Aripiprazole Crystals B of the present
invention can be prepared with certainty by heating Aripiprazole
Hydrate A for about 18 hours at 100.degree. C., and then heating it
for about 3 hours at 120.degree. C. The Anhydrous Aripiprazole
Crystals B of the present invention can also be obtained if the
heating time is extended still further, but this may not be
economical.
When small particle size is not required for the formulation, e.g.,
when drug substance is being manufactured for injectable or oral
solution formulations, Anhydrous Aripiprazole Crystal B can be also
obtained the following process.
The inventors also discovered that it is possible to obtain
anhydrous aripiprazole crystals by heating conventional
aripiprazole hydrate or conventional anhydrous aripiprazole
crystals to a specific temperature but this process does not yield
Anhydrous Aripiprazole Crystal B crystalline substance suitable for
commercial use in the formulation of solid oral dose
formulations.
Furthermore, the Anhydrous Aripiprazole Crystals B of the present
invention are prepared for example by heating conventional
anhydrous aripiprazole crystals at 90-125.degree. C. The heating
time is generally about 3-50 hours, but cannot be stated
unconditionally since it differs depending on heating temperature.
The heating time and heating temperature are inversely related, so
that for example the heating time will be longer the lower the
heating temperature, and shorter the higher the heating
temperature.
Specifically, if the heating temperature of the anhydrous
aripiprazole crystals is 100.degree. C., the heating time can be
about 4 hours, and if the heating temperature is 120.degree. C. the
heating time can be about 3 hours.
In addition to Aripiprazole Hydrate A and Anhydrous Aripiprazole
Crystals B mentioned above, the present invention provides
Anhydrous Aripiprazole Crystals C to G as follows.
1. The present invention relates to anhydrous aripiprazole crystals
(hereinafter referred to as "type C crystals of anhydrous
aripiprazole") having the following physicochemical properties (1)
to (5):
(1) an endothermic curve which is substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 8;
(2) an .sup.1H-NMR spectrum which is substantially identical to the
.sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 9;
(3) a powder X-ray diffraction spectrum which is substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
10;
(4) an IR spectrum which is substantially identical to the IR (KBr)
shown in FIG. 11; and
(5) a solid .sup.13C-NMR spectrum which is substantially identical
to the solid .sup.13C-NMR spectrum shown in FIG. 12.
2. The present invention relates to anhydrous aripiprazole crystals
(hereinafter referred to as "type D crystals of anhydrous
aripiprazole") having the following physicochemical properties (6)
to (10):
(6) an endothermic curve which is substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 13;
(7) an .sup.1H-NMR spectrum which is substantially identical to the
.sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 14;
(8) a powder X-ray diffraction spectrum which is substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
15;
(9) an IR spectrum which is substantially identical to the IR (KBr)
shown in FIG. 16; and
(10) a solid .sup.13C-NMR spectrum which is substantially identical
to the .sup.13C-NMR spectrum shown in FIG. 17.
3. The present invention relates to anhydrous aripiprazole crystals
(hereinafter referred to as "type E crystals of anhydrous
aripiprazole") having the following physicochemical properties (11)
to (14):
(11) an endothermic curve which is substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 18;
(12) an .sup.1H-NMR spectrum which is substantially identical to
the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 19;
(13) a powder X-ray diffraction spectrum which is substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
20; and
(14) an IR spectrum which is substantially identical to the IR
(KBr) shown in FIG. 21.
4. The present invention relates to anhydrous aripiprazole crystals
(hereinafter referred to as "type F crystals of anhydrous
aripiprazole") having the following physicochemical properties (15)
to (18):
(15) an endothermic curve which is substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 22;
(16) an .sup.1H-NMR spectrum which is substantially identical to
the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 23;
(17) a powder X-ray diffraction spectrum which is substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
24; and
(18) an IR spectrum which is substantially identical to the IR
(KBr) shown in FIG. 25.
5. The present invention relates a process for preparing anhydrous
aripiprazole crystals stated in the aforementioned item 1,
characterized by heating anhydrous aripiprazole crystals at a
temperature being higher than 140.degree. C. and lower than
150.degree. C.
6. The present invention relates a process for preparing anhydrous
aripiprazole crystals stated in the aforementioned item 2,
characterized by recrystallizing from toluene.
7. The present invention relates to a process for preparing
anhydrous aripiprazole crystals stated in the aforementioned item
3, characterized by heating and dissolving anhydrous aripiprazole
crystals in acetonitrile, and cooling it.
8. The present invention relates to a process for preparing
anhydrous aripiprazole crystals stated in the aforementioned item
4, characterized by heating a suspension of anhydrous aripiprazole
crystals in acetone.
9. The present invention relates to a pharmaceutical composition
containing at least one anhydrous aripiprazole crystals selected
from the group consisting of the anhydrous aripiprazole crystals
stated in the aforementioned item 1, the anhydrous aripiprazole
crystals stated in the aforementioned item 2, the anhydrous
aripiprazole crystals stated in the aforementioned item 3, the
anhydrous aripiprazole crystals stated in the aforementioned item
4, and the anhydrous aripiprazole crystals stated in the
after-mentioned item 10, together with pharmaceutically acceptable
carriers.
10. The present invention relates to anhydrous aripiprazole
crystals (hereinafter referred to as "type G crystals of anhydrous
aripiprazole") having the following physicochemical properties (19)
to (22):
(19) an endothermic curve which is substantially identical to the
thermogravimetric/differential thermal analysis (heating rate;
5.degree. C./min.) endothermic curve shown FIG. 26.
(20) an .sup.1H-NMR spectrum which is substantially identical to
the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 27.
(21) a power X-ray diffraction spectrum which is substantially
identical to the power X-ray diffraction spectrum shown in FIG. 28;
and
(22) an IR spectrum which is substantially identical to the IR
(Kbr) shown in FIG. 29.
11. The present invention relates to a process for preparing
anhydrous aripiprazole crystals stated in the aforementioned item
10, characterized by putting glassy state of Anhydrous Aripiprazole
in a sealed vessel and keeping it at room temperature for at least
2 weeks.
12. The present invention relates to a process for the preparation
of granules, characterized by wet granulating conventional
Anhydrous Aripiprazole Crystals or Anhydrous Aripiprazole Crystals
B, C, D, E, F or G, drying the obtained granules at 70 to
100.degree. C. and sizing it, then drying the sized granules at 70
to 100.degree. C. again.
13. The present invention relates to a process for the
pharmaceutical solid oral preparation, characterized by drying a
pharmaceutical solid oral preparation comprising conventional
Anhydrous Aripiprazole Crystals or Anhydrous Aripiprazole Crystals
B, C, D, E, F or G, and one or more pharmaceutically acceptable
carriers at 70 to 100.degree. C.
14. The present invention relates to a pharmaceutical solid oral
preparation comprising Anhydrous Aripiprazole Crystals B, C, D, E,
F or G and one or more pharmaceutically acceptable carriers,
wherein said pharmaceutical solid oral preparation has at least one
dissolution rate selected from the group consisting 60% or more at
pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes,
and 55% or more at pH 5.0 after 60 minutes.
15. The present invention relates to a pharmaceutical solid oral
preparation having at least one dissolution rate selected from the
group consisting 60% or more at pH 4.5 after 30 minutes, 70% or
more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60
minutes.
16. The present invention relates to a pharmaceutical solid oral
preparation obtained by wet granulating conventional Anhydrous
Aripiprazole Crystals, drying the obtained granules at 70 to
100.degree. C. and sizing it, then drying the sized granules at 70
to 100.degree. C. again, and the pharmaceutical solid oral
preparation has at least one dissolution rate selected from the
group consisting 60% or more at pH 4.5 after 30 minutes, 70% or
more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60
minutes.
17. The present invention relates to a pharmaceutical solid oral
preparation obtained by drying a pharmaceutical solid oral
preparation comprising conventional Anhydrous Aripiprazole Crystals
and one or more pharmaceutically acceptable carriers at 70 to
100.degree. C., and the pharmaceutical solid oral preparation has
at least one dissolution rate selected from the group consisting
60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after
60 minutes, and 55% or more at pH 5.0 after 60 minutes.
18. The present invention relates to a process for the preparation
of granules, characterized by wet granulating conventional
Aripiprazole Hydrate Crystals, drying the obtained granules at 70
to 100.degree. C. and sizing it, then drying the sized granules at
70 to 100.degree. C. again.
19. The present invention relates to a process for the
pharmaceutical solid oral preparation, characterized by drying a
pharmaceutical solid oral preparation comprising conventional
Aripiprazole Hydrate Crystals and one or more pharmaceutically
acceptable carriers at 70 to 100.degree. C.
20. The present invention relates to a pharmaceutical solid oral
preparation obtained by wet granulating conventional Aripiprazole
Hydrate Crystals, drying the obtained granules at 70 to 100.degree.
C. and sizing it, then drying the sized granules at 70 to
100.degree. C. again, and the pharmaceutical solid oral preparation
has at least one dissolution rate selected from the group
consisting 60% or more at pH 4.5 after 30 minutes, 70% or more at
pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60
minutes.
21. The present invention relates to a pharmaceutical solid oral
preparation obtained by drying a pharmaceutical solid oral
preparation comprising conventional Aripiprazole Hydrate Crystals
and one or more pharmaceutically acceptable carriers at 70 to
100.degree. C., and the pharmaceutical solid oral preparation has
at least one dissolution rate selected from the group consisting
60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after
60 minutes, and 55% or more at pH 5.0 after 60 minutes.
The Type C to F crystals of anhydrous aripiprazole of the present
invention correspond to the Type-III to VI crystals of anhydrous
aripiprazole disclosed in JP-2001-348276.
Type C Crystals of Anhydrous Aripiprazole
Type C crystals of anhydrous aripiprazole of the present invention
have the following physicochemical properties (1) to (5):
(1) an endothermic curve which is substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 8, more
particularly, it has an endothermic peak around 150.2.degree.
C.;
(2) an .sup.1H-NMR spectrum which is substantially identical to the
.sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 9.
Specifically, it has characteristic peaks at 1.55-1.63 ppm (m, 2H),
1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,
4H+DMSO), 2.78 ppm (t, J=7, 4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz,
4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49
ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),
7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s,
1H);
(3) a powder X-ray diffraction spectrum which is substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
10. Specifically, it has characteristic peaks at
2.theta.=12.6.degree., 13.7.degree., 15.4.degree., 18.1.degree.,
19.0.degree., 20.6.degree., 23.5.degree. and 26.4.degree.;
(4) an IR spectrum which is substantially identical to the IR (KBr)
spectrum shown in FIG. 11. Specifically, it has clear infrared
absorption bands at 2939, 2804, 1680, 1375 and 780 cm.sup.-1;
and
(5) a solid .sup.13C-NMR spectrum which is substantially identical
to the solid .sup.13C-NMR spectrum shown in FIG. 12, specifically,
it has characteristic peaks at 32.8 ppm, 60.8 ppm, 74.9 ppm, 104.9
ppm, 152.2 ppm, 159.9 ppm and 175.2 ppm.
Preparation Method of Type C Crystals of Anhydrous Aripiprazole
Type C crystals of anhydrous aripiprazole of the present invention
is prepared, for example by heating an anhydrous aripiprazole at a
temperature of higher than 140.degree. C. and lower than
150.degree. C.
Anhydrous aripiprazole used as the raw material may be conventional
anhydrous aripiprazole crystals, for example, type-I crystals of
anhydrous aripiprazole, type-II crystals of anhydrous aripiprazole
crystals and the like, and these anhydrous aripiprazoles may be
either purified products or crude materials. Alternatively, type B
crystals of anhydrous aripiprazole, type D crystals of anhydrous
aripiprazole, type E crystals of anhydrous aripiprazole, type F
crystals of anhydrous aripiprazole, or type G crystals of anhydrous
aripiprazole being prepared in the present invention can be used as
the raw material of anhydrous aripiprazole. These anhydrous
aripiprazoles can be used singly or in combination of at least 2
kinds thereof.
Heating temperature is generally higher than 140.degree. C. and
lower than 150.degree. C., preferably at 142-148.degree. C., and
heating time is generally for 15 minutes to 3 hours, preferably for
30 minutes to 1 hour.
When, an anhydrous aripiprazole is heated at the above-mentioned
temperature, then type C crystals of anhydrous aripiprazole are
formed.
Thus obtained type C crystals of anhydrous aripiprazole can be
isolated and purified by well-known methods. For example, after
heating the anhydrous aripiprazole at the above-mentioned
temperature, and by cooling to a room temperature, then type C
crystals of anhydrous aripiprazole, having 100% of purity can be
obtained.
Type D Crystals of Anhydrous Aripiprazole
Type D crystals of anhydrous aripiprazole of the present invention
have the following physicochemical properties (6) to (10):
(6) an endothermic curve which is substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 13; more
particularly, it has an endothermic peak around 136.8.degree. C.
and 141.6.degree. C.;
(7) an .sup.1H-NMR spectrum which is substantially identical to the
.sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 14.
Specifically, it has characteristic peaks at 1.55-1.63 ppm (m, 2H),
1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,
4H+DMSO), 2.78 ppm (t, J=7, 4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz,
4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49
ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),
7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s,
1H);
(8) a powder X-ray diffraction spectrum which is substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
15. Specifically, it has characteristic peaks at
2.theta.=8.7.degree., 11.6.degree., 16.3.degree., 17.7.degree.,
18.6.degree., 20.3.degree., 23.4.degree. and 25.0.degree.;
(9) an IR spectrum which is substantially identical to the IR (KBr)
spectrum shown in FIG. 16. Specifically, it has clear infrared
absorption bands at 2946, 1681, 1375, 1273, 1175 and 862 cm.sup.-1;
and
(10) a solid .sup.13C-NMR spectrum which is substantially identical
to the solid .sup.13C-NMR spectrum shown in FIG. 17, specifically,
it has characteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1
ppm, 152.4 ppm, 158.4 ppm, and 174.1 ppm.
Preparation Method of Type D Crystals of Anhydrous Aripiprazole
Type D crystals of anhydrous aripiprazole of the present invention
is prepared, for example, by recrystallization of anhydrous
aripiprazole from toluene. Specifically, an anhydrous aripiprazole
is added to toluene, further heated and dissolved, then thus
obtained solution is cooled. By such procedures, type D crystals of
anhydrous aripiprazole of the present invention is separated out as
crystals in toluene.
Anhydrous aripiprazole to be used as the raw materials may be
conventional anhydrous aripiprazole, for example type-I crystals of
anhydrous aripiprazole, type-II crystals of anhydrous aripiprazole
and the like, and these anhydrous aripiprazoles may be either
purified products or crude materials. Alternatively, type B
crystals of anhydrous aripiprazole, type C crystals of anhydrous
aripiprazole, type E crystals of anhydrous aripiprazole, type F
crystals of anhydrous aripiprazole, or type G crystals of anhydrous
aripiprazole being prepared in the present invention can be used as
the raw material for anhydrous aripiprazoles. These anhydrous
aripiprazoles can be used singly or in combination of at least 2
kinds thereof.
When the solution obtained by heating and dissolving is cooled,
type D crystals of anhydrous aripiprazole may be added as a seed
crystal to said solution. Further, the seed crystal may be formed
by cooling gradually said solution being obtained by heating and
dissolving. In the presence of the seed crystal, type D crystals of
anhydrous aripiprazole may be separated out.
Thus separated out type D crystals of anhydrous aripiprazole can be
isolated and purified in accordance with well-known methods. By
such procedures, type D crystals of anhydrous aripiprazole, having
the purity of 100% can be obtained.
Type E Crystals of Anhydrous Aripiprazole
Type E crystals of anhydrous aripiprazole of the present invention
have the following physicochemical properties (11) to (14):
(11) an endothermic curve which is substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 18,
specifically, it has an endothermic peak around 146.5.degree.
C.;
(12) an .sup.1H-NMR spectrum which is substantially identical to
the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 19.
Specifically, it has characteristic peaks at 1.55-1.63 ppm (m, 2H),
1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,
4H+DMSO), 2.78 ppm (t, J=7, 4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz,
4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49
ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),
7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s,
1H);
(13) a powder X-ray diffraction spectrum which is substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
20. Specifically, it has characteristic peaks at
2.theta.=8.0.degree., 13.7.degree., 14.6.degree., 17.6.degree.,
22.5.degree. and 24.0.degree.; and
(14) an IR spectrum which is substantially identical to the IR
(KBr) spectrum shown in FIG. 21. Specifically, it has clear
infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969 and
774 cm.sup.-1.
Preparation Method of Type E Crystals of Anhydrous Aripiprazole
Type E crystals of anhydrous aripiprazole of the present invention
is prepared, for example by recrystallization of the anhydrous
aripiprazole from acetonitrile. Specifically, by adding a
well-known anhydrous aripiprazole to acetonitrile, heating and
dissolving, then the solution thus obtained may be cooled. In
accordance with such procedures, type E crystals of anhydrous
aripiprazole of the present invention are separated out in the
acetonitrile.
When a conventional anhydrous aripiprazole is added to
acetonitrile, type-I crystals of anhydrous aripiprazole, type-II
crystals of anhydrous aripiprazole and type D crystals of anhydrous
aripiprazole are separated out, other than type E crystals of
anhydrous aripiprazole. Plate crystals being separated out from the
acetonitrile solution at 70.degree. C. are type-I crystals, type-II
crystals and type D crystals, while type E crystals are
precipitated out as needle crystals. When the acetonitrile solution
after separated out of these crystals is heated again (for example,
heated at over 75.degree. C.), the plate crystals (type-I crystals,
type-II crystals and type D crystals) are quickly dissolved, on the
contrary, the needle form crystals (type E crystals) do not
dissolved. Additionally, when the acetonitrile solution is cooled
again, then needle form crystals (type E crystals) are further
separated out around the needle form crystals (type E crystals)
previously precipitated as the seed crystals. Thus, type E crystals
of anhydrous aripiprazole can be precipitated in the acetonitrile
solution.
Anhydrous aripiprazoles used as the raw materials may be
conventional anhydrous aripiprazoles, for example any one of type-I
crystals of anhydrous aripiprazole and type-II crystals of
anhydrous aripiprazole and the like, and these anhydrous
aripiprazoles may be either purified products or crude materials.
Alternatively, type B crystals of anhydrous aripiprazole, type C
crystals of anhydrous aripiprazole, type D crystals of anhydrous
aripiprazole, type F crystals of anhydrous aripiprazole, or type G
crystals of anhydrous aripiprazole can be used as the raw materials
for anhydrous aripiprazoles. These anhydrous aripiprazoles can be
used singly or in combination of at least 2 kinds thereof.
When the acetonitrile solution obtained by heating (heating and
dissolving) is cooled, the type E crystals of aripiprazole may be
added as a seed crystal to said solution. Further, the seed crystal
may be formed by cooling gradually said acetonitrile solution which
was obtained by heating.
Thus separated out type E crystals of anhydrous aripiprazole can be
isolated and purified in accordance with well-known methods. By
such procedures, type E crystals of anhydrous aripiprazole, having
the purity of 100% can be obtained.
Type F Crystals of Anhydrous Aripiprazole
Type F crystals of anhydrous aripiprazole of the present invention
have the following physicochemical properties (15) to (18):
(15) an endothermic curve which is substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 22,
specifically, it has an endothermic peaks around 137.5.degree. C.
and 149.8.degree. C.;
(16) an .sup.1H-NMR spectrum which is substantially identical to
the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 23.
Specifically, it has characteristic peaks at 1.55-1.63 ppm (m, 2H),
1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,
4H+DMSO), 2.78 ppm (t, J=7, 4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz,
4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49
ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H),
7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s,
1H);
(17) a powder X-ray diffraction spectrum which is substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
24. Specifically, it has characteristic peaks at
2.theta.=11.3.degree., 13.3.degree., 15.4.degree., 22.8.degree.,
25.2.degree. and 26.9.degree., and
(18) Having an IR spectrum which is substantially identical to the
IR (KBr) spectrum shown in FIG. 25. Specifically, it has clear
infrared absorption bands at 2940, 2815, 1679, 1383, 1273, 1177,
1035, 963 and 790 cm.sup.-1.
Preparation Method of Type F Crystals of Anhydrous Aripiprazole
Type F crystals of anhydrous aripiprazole of the present invention
is prepared, for example by suspending an anhydrous aripiprazole in
acetone, and thus obtained acetone suspension is heated.
Anhydrous aripiprazoles used as the raw materials may be
conventional anhydrous aripiprazole, for example any one of type-I
crystals of anhydrous aripiprazole and type-II crystals of
anhydrous aripiprazole and the like, and these anhydrous
aripiprazoles may be either purified products or crude materials.
Alternatively, type B crystals of anhydrous aripiprazole, type C
crystals of anhydrous aripiprazole, type D crystals of anhydrous
aripiprazole, type E crystals of anhydrous aripiprazole, or type G
crystals of anhydrous aripiprazole prepared in the present
invention can be used as the raw materials for anhydrous
aripiprazoles. These anhydrous aripiprazoles can be used singly or
in combination of at least 2 kinds thereof.
Heating temperature of the acetone suspension may be generally
about the boiling point of acetone, and heating time is generally 5
to 10 hours. When the acetone suspension is heated about the
boiling point of acetone, then type F crystals of anhydrous
aripiprazole is formed, the crystals are isolated by filtration
with heating. Isolation of the crystals may be carried out in
accordance with well-known methods. By such procedures, type F
crystals of anhydrous aripiprazole, having the purity of 100% can
be obtained.
Type G Crystals of Anhydrous Aripiprazole
Type G crystals of anhydrous aripiprazole of the present invention
have the following physicochemical properties (19) to (22):
(19) an endothermic curve which is substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 26, more
particularly, it has an endothermic peak around 141.0.degree. C.
and an exothermic peak around 122.7.degree. C.;
(20) an .sup.1H-NMR spectrum which is substantially identical to
the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 27.
Specifically, it has characteristic peaks at 1.55-1.63 ppm (m, 2H),
1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,
4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H),
3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm
(dd, J=8.4 Hz, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz,
1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32
ppm (m, 2H) and 10.00 ppm (s, 1H);
(21) a powder X-ray diffraction spectrum which is substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
28. Specifically, it has characteristic peaks at
2.theta.=10.1.degree., 12.8.degree., 15.2.degree., 17.0.degree.,
17.5.degree., 19.1.degree., 20.1.degree., 21.2.degree.,
22.4.degree., 23.3.degree., 24.5.degree. and 25.8.degree.; and
(22) an IR spectrum which is substantially identical to the IR
(KBr) spectrum shown in FIG. 29. Specifically, it has clear
infrared absorption bands at 2942, 2813, 1670, 1625, 1377, 1195,
962 and 787 cm.sup.-1.
Preparation Method of Type G Crystals of Anhydrous Aripiprazole
Type G crystals of anhydrous aripiprazole of the present invention
can be prepared, for example by putting glassy state of anhydrous
aripiprazole in a sealed vessel and leaving to stand it at room
temperature for at least two weeks, preferably two weeks to six
months. Further, glassy state of anhydrous aripiprazole as starting
material can be obtained by heating and melting anhydrous
aripiprazole at around 170.degree. C., then cooling it to room
temperature.
Anhydrous aripiprazole used as the raw material may be well-known
anhydrous aripiprazole crystals, for example, any one of type-I
crystals of anhydrous aripiprazole and type-II crystals of
anhydrous aripiprazole and the like, and these anhydrous
aripiprazoles may be either purified products or crude materials.
Alternatively, type B crystals of anhydrous aripiprazole, type C
crystals of anhydrous aripiprazole, type D crystals of anhydrous
aripiprazole, type E crystals of anhydrous aripiprazole, or type F
crystals of anhydrous aripiprazole being prepared in the present
invention can be used as the raw material of anhydrous
aripiprazoles. These anhydrous aripiprazoles can be used singly or
in combination of at least 2 kinds thereof.
Thus obtained type G crystals of anhydrous aripiprazole can be
isolated and purified by well-known methods. For example, glassy
state of anhydrous aripiprazole leave to stand according to the
above-mentioned method, then type G crystals of anhydrous
aripiprazole, having 100% of purity can be obtained.
Type C crystals of anhydrous aripiprazole, type D crystals of
anhydrous aripiprazole, type E crystals of anhydrous aripiprazole,
type F crystals of anhydrous aripiprazole and type G crystals of
anhydrous aripiprazole of the present invention neither easily
convert into hydrates thereof, nor substantially decrease the
original solubility, even when they are stored for a long period of
time.
In accordance with the present invention, methods for preparing
anhydrous aripiprazole crystals having high purity, which can apply
in an industrial scale with a good repeatability is provided.
In accordance with the present invention, pharmaceutical
compositions comprising anhydrous aripiprazole crystals are
provided, of which the solubility does not decrease, and of which
the stability can keep excellent, even if they are stored for long
time.
The anhydrous aripiprazole crystals which are the raw material for
preparing the Anhydrous Aripiprazole Crystals B to G of the present
invention are prepared for example by Method a or b below.
"Method a": Process for Preparing Crude Aripiprazole Crystals
Conventional Anhydrous Aripiprazole crystals are prepared by
well-known methods, as described in Example 1 of Japanese
Unexamined Patent Publication No. 191256/1990.
A suspension of 47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril,
35 g of sodium iodide with 600 ml of acetonitrile was refluxed for
30 minutes. To this suspension was added 40 g of
1-(2,3-dichlorophenyl)piperazine and 33 ml of triethylamine and the
whole mixture was further refluxed for 3 hours. After the solvent
was removed by evaporation, the residue thus obtained was dissolved
in chloroform, washed with water then dried with anhydrous
magnesium sulfate. The solvent was removed by evaporation, and the
residue thus obtained was recrystallized from ethanol twice, to
yield 57.1 g of
7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydroc-
arbostyril.
Colorless Flake Crystals
Melting point: 139.0-139.5.degree. C.
"Method b": Process for Preparing Conventional Anhydrous
Aripiprazole
The Method b is described in the Proceedings of the 4th
Japanese-Korean Symposium on Separation Technology (Oct. 6-8,
1996).
Furthermore, the Anhydrous Aripiprazole Crystals B of the present
invention are prepared for example by heating conventional
aripiprazole hydrate at 90-125.degree. C. The heating time is
generally about 3-50 hours, but cannot be stated unconditionally
since it differs depending on heating temperature. The heating time
and heating temperature are inversely related, so that for example
the heating time will be longer the lower the heating temperature,
and shorter the higher the heating temperature. Specifically, if
the heating temperature of the aripiprazole hydrate is 100.degree.
C., the heating time can be about 24 hours, while if the heating
temperature is 120.degree. C., the heating time can be about 3
hours.
The aripiprazole hydrate which is the raw material for preparing
the Anhydrous Aripiprazole Crystals B of the present invention is
prepared for example by Method c below.
"Method c": Process for Preparing Conventional Hydrate
Aripiprazole hydrate is easily obtained by dissolving the anhydrous
aripiprazole crystals obtained by Method a above in a hydrous
solvent, and heating and then cooling the resulting solution. Using
this method, aripiprazole hydrate is precipitated as crystals in
the hydrous solvent.
An organic solvent containing water is usually used as the hydrous
solvent. The organic solvent should be one which is miscible with
water, such as for example an alcohol such as methanol, ethanol,
propanol or isopropanol, a ketone such as acetone, an ether such as
tetrahydrofuran, dimethylformamide, or a mixture thereof, with
ethanol being particularly desirable. The amount of water in the
hydrous solvent can be 10-25% by volume of the solvent, or
preferably close to 20% by volume.
Medicinal Composition
A medicinal composition of the present invention will contain
Anhydrous Aripiprazole Crystals B, C, D, E, F and G in a
pharmaceutically acceptable carrier or combination of carriers.
Carriers which are pharmaceutically acceptable include diluents and
excipients generally used in pharmaceuticals, such as fillers,
extenders, binders, moisturizers, disintegrators, surfactants, and
lubricants.
The medicinal composition of the present invention may be
formulated as an ordinary medicinal preparation, for example in the
form of tablets, flashmelt tablets, pills, powder, liquid,
suspension, emulsion, granules, capsules, suppositories or as an
injection (liquid, suspension, etc.).
When a tablet formulation is used, a wide variety of carriers that
are known in the field can be used. Examples include lactose,
saccharose, sodium chloride, glucose, xylitol, mannitol,
erythritol, sorbitol, urea, starch, calcium carbonate, kaolin,
crystal cellulose, silic acid and other excipients; water, ethanol,
propanol, simple syrup, glucose liquid, starch liquid, gelatin
solution, carboxymethyl cellulose, shellac, methyl cellulose,
potassium phosphate, polyvinyl pyrolidone and other binders; dried
starch, sodium alginate, agar powder, laminaran powder, sodium
bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid
esters, sodium lauryl sulfate, monoglyceride stearate, starch,
lactose and other disintegrators; saccharose, stearin, cacao
butter, hydrogenated oil and other disintegration inhibitors;
quaternary ammonium salt, sodium lauryl sulfate and other
absorption promoters; glycerine, starch and other moisture
retainers; starch, lactose, kaolin, bentonite, colloidal silic acid
and other adsorbents; and refined talc, stearate, boric acid
powder, polyethylene glycol and other lubricants and the like.
Tablets can also be formulated if necessary as tablets with
ordinary coatings, such as sugar-coated tablets, gelatin-coated
tablets, enteric coated tablets and film coated tablets, as well as
double tablets and multilayered tablets.
When a pill formulation is used, a wide variety of carriers that
are known in the field can be used. Examples include glucose,
lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc
and other excipients; gum arabic powder, traganth powder, gelatin,
ethanol and other binders; and laminaran, agar and other
disintegrators and the like.
When a suppository formulation is used, a wide variety of carriers
that are known in the field can be used. Examples include
polyethylene glycol, cacao butter, higher alcohol, esters of higher
alcohol, gelatin semi-synthetic glyceride and the like.
Capsules are prepared according to ordinary methods by mixing
anhydrous aripiprazole crystals with the various carriers described
above and packing them in hard gelatin capsules, soft capsules,
hydroxypropylmethyl cellulose capsules (HPMC capsules) and the
like.
In addition, colorants, preservatives, perfumes, flavorings,
sweeteners and the like as well as other drugs may be included in
the medicinal composition.
In case of forming the pharmaceutical solid oral preparation in the
form of granules, it can be prepared by wet granulating a mixed
powder of granulating ingredients comprising, anhydrous
aripiprazole crystals (conventional anhydrous aripiprazole crystals
or anhydrous aripiprazole crystals selected from the group
consisting of anhydrous aripiprazole type B, C, D, E, F and G
crystals) and various carriers which are heretofore well-known in
this field, such as excipients, disintegrators, disintegration
inhibitors, humectants, absorption accelerators, adsorbents,
lubricants, colorants and the like (for the examples of these
agents, those of previously mentioned can be referred to) by adding
a liquid (generally, water or an aqueous solution containing
binding agents). As for the wet granulation, there are various
methods are included, for example, fluidized bed granulation,
kneading granulation, extruding granulation, rotating granulation
and the like can be mentioned. Among these methods, in case of
conducting the fluidized bed granulation, the granulating
ingredients containing various carriers are mixed with inlet air,
then upon continued fluidizing the granulating ingredients and the
liquid is sprayed to conduct granulation. In case of conducting the
kneading granulation, the granulating ingredients containing
various carriers are mixed by agitation, then upon continued
agitating the granulating ingredients, granulation is conducted by
adding the liquid. After the granulation, if necessary, the
obtained granules are sized to make them to the desired size by use
of a suitable sieve or a mill having suitable screen size. The
granules thus obtained by such a method are dried again in addition
to usual drying being conducted when preparing the granules. As for
the drying methods, various methods can be applied, for example,
methods by use of a fluidized bed dryer, a fan dryer, a vacuum
dryer and the like can be mentioned. Generally, drying methods can
be conducted under conventional conditions, for example, in case of
using the fluidized bed dryer, drying procedure is conducted with
an air flow of 0.5 m.sup.3/min to 50 m.sup.3/min, an inlet air
temperature at 70 to 100.degree. C. for 10 min to 1 hour. After
dried, the granules are subjected to size, then further dried. In
case of using the fluidized bed dryer or fan dryer or the like, the
drying procedure is conducted under the conditions with an air flow
of 0.5 m.sup.3/min to 50 m.sup.3/min, an inlet air temperature at
70 to 100.degree. C. for 1 to 6 hours. In case of using the vacuum
dryer, the drying procedure is conducted under the conditions of
reduced pressure of about at 0-10 torr of degree of vacuum at 70 to
100.degree. C. of jacket temperature for 1 to 6 hour.
The thus prepared granules may be used as they are for the
pharmaceutical solid oral preparations, or if necessary, they may
be shaped in the form of tablets. Further, the dried granules dried
by usual manner are shaped in the form of tablets, then they may be
dried again.
The thus prepared pharmaceutical solid oral preparation comprising
anhydrous aripiprazole crystals hardly changes to hydrates even if
they are stored for a long period of time, therefore the
pharmaceutical solid oral preparation, of which dissolution rate
does not hardly lowered (dissolution rate to maintain maximum drug
concentration (Cmax): 60% or higher dissolution rate obtained after
30 minutes at pH 4.5, 70% or higher dissolution rate obtained after
60 minutes at pH 4.5, or 55% or higher dissolution rate obtained
after 60 minutes at pH 5.0) can be provided.
Another pharmaceutical solid oral preparation can be provided by
granulating a conventional aripiprazole hydrate crystals by a
method similar to that of mentioned above, and dried by usual
manner under similar conditions, then dried again. Alternatively,
the dried granules dried by usual manner are shaped to tablets
form, then they are dried again, then pharmaceutical solid oral
preparations of which dissolution rate does not lowered
(dissolution rate to maintain maximum drug concentration (Cmax):
60% or higher dissolution rate obtained after 30 minutes at pH 4.5,
70% or higher dissolution rate obtained after 60 minutes at pH 4.5
or 55% or higher dissolution rate obtained after 60 minutes at pH
5.0) can be provided. These facts can be understood that, the
conventional anhydrous aripiprazole crystals or the aripiprazole
hydrate crystals contained in the pharmaceutical solid oral
preparation are changed to "B type crystals" of anhydrous
aripiprazole by drying twice.
The amount of Anhydrous Aripiprazole Crystals B, C, D, E, F and G
that should be included in the medicinal composition of the present
invention can be selected from a wide range suitable for the
indication sought to be treated. Generally, the Anhydrous
Aripiprazole Crystals B should be present in about 1-70% by weight
or particularly about 1-30% by weight based on the medicinal
composition.
The method of administration of the medicinal composition of the
present invention may be adjusted to suit, for example, the
formulation of the drug product, the age, gender and other
conditions (including the severity thereof) of the patient. In the
case of tablets, pills, liquids, suspensions, emulsions, granules
and capsules, for example, administration is oral. In the case of
an injection, it is administered intravenously either by itself or
mixed with an ordinary replenisher such as glucose or amino acids,
or may also be administered by itself intramuscularly,
intracutaneously, subcutaneously or intraperitoneally, as
necessary. In the case of a suppository, administration is
intrarectal.
The dosage of the medicinal composition of the present invention is
selected depending on the usage, the age, gender and other
conditions of the patient, the severity of the condition and so
forth, but ordinarily the amount of anhydrous aripiprazole crystals
can be about 0.1-10 mg per 1 kg of body weight per day. The
preparation which is the unit of administration should contain in
the range of about 1-100 mg of Anhydrous Aripiprazole Crystals B,
more particularly 1-30 mg per unit dose.
The medicinal composition of the present invention is extremely
stable, with substantially no decrease in solubility even when
stored for long periods of time.
The medicinal composition of the present invention is effective in
the prevention and treatment of central nervous system disorders
such as schizophrenia and may also be effective in the treatment of
intractable (drug-resistant, chronic) schizophrenia with cognitive
impairment and intractable (drug-resistant, chronic) schizophrenia
without cognitive impairment, anxiety including mild anxiety, mania
including bipolar disorder acute mania and acute mania, bipolar
disorder, depression including bipolar disorder depression, autism,
Down's syndrome, attention deficit hyperactivity disorder (ADHD),
Alzheimer's disease, Parkinson's disease and other
neurodegenerative diseases, panic, obsessive compulsive disorder
(OCD), sleep disorders, sexual dysfunction, alcohol and drug
dependency, vomiting, motion sickness, obesity, miparticlee
headache and cognitive impairment.
Analytical Methods
(1) The .sup.1H-NMR spectrum was measured in DMSO-d.sub.6 using TMS
as the standard.
(2) Powder X-ray Diffraction
Using a Rigaku Denki RAD-2B diffraction meter, the powder x-ray
diffraction pattern was measured at room temperature using a Cu Ka
filled tube (35 kV 20 mA) as the x-ray source with a wide-angle
goniometer, a 1.degree. scattering slit, an 0.15 mm
light-intercepting slit, a graphite secondary monochromator and a
scintillation counter. Data collection was done in 2.theta.
continuous scan mode at a scan speed of 5.degree./minute in scan
steps of 0.02.degree. in the range of 3.degree. to 40.degree..
(3) The IR spectrum was measured by the KBr method.
(4) Thermogravimetric/Differential Thermal Analysis
Thermogravimetric/differential thermal analysis was performed using
a Seiko SSC 5200 control unit and a TG/DTA 220 simultaneous
differential thermal/thermogravimetric measurement unit. 5-10 mg
samples were placed in open aluminum pans and heated from
20.degree. C. to 200.degree. C. in a dry nitrogen atmosphere at a
heating rate of 5.degree. C./minute. .alpha.-alumina was used as
the standard substance.
(5) Differential Scanning Calorimetry
Thermogravimetric/differential thermal analysis was performed using
a Seiko SSC 5200 control unit and a DSC 220C differential scanning
calorimeter. 5-10 mg samples were placed in crimped aluminum pans
and heated from 20.degree. C. to 200.degree. C. in a dry nitrogen
atmosphere at a heating rate of 5.degree. C./minute.
.alpha.-alumina was used as the standard substance.
(6) Particle Size Measurement
0.1 g of the particles to be measured were suspended in a 20 ml
n-hexane solution of 0.5 g soy lecithin, and particle size was
measured using a size distribution meter (Microtrack HRA,
Microtrack Co.).
(7) Hygroscopicity Test Method
One g of the sample was accurately weighed in a weighing bottle
(diameter 5 cm), covered with kimwipes and left to rest in a
60.degree. C./100% RH environment (water/dessicator). 24 hours
later, the weighing bottle was removed, transferred to an
environment of a room temperature and about 30% RH (magnesium
chloride hexahydrate saturated water solution/dessicator) and left
to rest for 24 hours and the water content of the sample was
measured by the Karl Fischer method.
(8) Solid .sup.13C-NMR Spectrometry
Solid .sup.13C-NMR spectrum was measured under the conditions as
follows.
Measuring apparatus: CMX-360 Solid State NMR Spectrometer
(manufactured by Chemagnetic Inc.)
Computer: SPARC Station 2 (manufactured by SUN Microsystem,
Inc.)
OS, Software: Solalis 1.1.1 Rev. B (Registered trademark: UNIX),
Spinsight Ver. 2.5
Name of measured pulse: TOSS method (TOSS is a program name of the
apparatus) among CP/MAS method.
Width of measured puls: 90.degree. puls was used under the
condition of CP.
Measuring sample tube: Test tube made of zirconia, having the
outside diameter of 7.5 mm, and inside capacity of 0.8 ml
Revolution: 4250 Hz (Revolution per second
Contact time: 1 msec.
Waiting time: 20 sec.
Integrated times: 512 times
Measuring temperature: About 25.degree. C. temperature of outside
of test tube)
External standard: Methyl group (.delta. 17.3) of hexamethylbenzene
was used as the external standard.
The present invention is explained in more detail below using
reference examples, examples, sample preparations and formulation
examples.
Reference Example 1
19.4 g of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril and 16.2 g of
1-(2,3-dichlorophenyl) piperadine 1 hydrochloride were added to
8.39 g of potassium carbonate dissolved in 140 ml of water, and
circulated for 3 hours under agitation. After reaction the mixture
was cooled and the precipitated crystals filtered out. These
crystals were dissolved in 350 ml of ethyl acetate, and about 210
ml of water/ethyl acetate azeotrope removed under reflux. The
remaining solution was cooled, and the precipitated crystals
filtered out. The resulting crystals were dried for 14 hours at
60.degree. C. to produce 20.4 g (74.2%) of raw aripiprazole.
30 g of the raw aripiprazole obtained above was recrystallized from
450 ml of ethanol according to the methods described in Japanese
Unexamined Patent Publication No. 191256/1990, and the resulting
crystals dried for 40 hours at 80.degree. C. to obtain anhydrous
aripiprazole crystals. The yield was 29.4 g (98.0%).
The melting point (mp) of these anhydrous aripiprazole crystals was
140.degree. C., matching the melting point of the anhydrous
aripiprazole crystals described in Japanese Unexamined Patent
Publication No. 191256/1990.
When these crystals were left for 24 hours in a dessicator set at
humidity 100%, temperature 60.degree. C., they exhibited
hygroscopicity of 3.28% (see Table 1 below).
Reference Example 2
6930 g of the intermediate raw aripiprazole obtained in Reference
Example 1 was heat dissolved in 138 liters of hydrous ethanol
(water content 20%) according to the method presented at the 4th
Japanese-Korean Symposium on Separation Technology, gradually (2-3
hours) cooled to room temperature, and then chilled to near
0.degree. C. The precipitated crystals were filtered out, producing
about 7200 g of aripiprazole hydrate (wet state).
The wet-state aripiprazole hydrate crystals obtained above were
dried for 30 hours at 80.degree. C. to obtain 6480 g (93.5%) of
conventional anhydrous aripiprazole crystals. The melting point
(mp) of these crystals was 139.5.degree. C. These crystals were
confirmed by the Karl Fischer method to be anhydrous, with a
moisture value of 0.03%.
When left for 24 hours in a dessicator set at humidity 100%,
temperature 60.degree. C., these crystals exhibited hygroscopicity
of 1.78% (see Table 1 below).
Reference Example 3
820 g of the intermediate wet-state aripiprazole hydrate obtained
in Reference Example 2 was dried for 2 hours at 50.degree. C. to
obtain 780 g of aripiprazole hydrate crystals. These crystals had a
moisture value of 3.82% according to the Karl Fischer method. As
shown in FIG. 6, thermogravimetric/differential thermal analysis
revealed endothermic peaks at 75.0, 123.5 and 140.5.degree. C.
Because dehydration began near 70.degree. C., there was no clear
melting point (mp).
As shown in FIG. 7, the powder x-ray diffraction spectrum of
aripiprazole hydrate obtained by this method exhibited
characteristic peaks at 2.theta.=12.6.degree., 15.1.degree.,
17.4.degree., 18.2.degree., 18.7.degree., 24.8.degree. and
27.5.degree..
The powder x-ray diffraction spectrum of this aripiprazole hydrate
was identical to the powder x-ray diffraction spectrum of
aripiprazole hydrate presented at the 4th Joint Japanese-Korean
Symposium on Isolation Technology.
Reference Example 4
Preparation of 15 mg tablets containing type I crystals of
anhydrous aripiprazole obtained in Reference Example 2.
Type-I crystals of anhydrous aripiprazole (525 g), lactose (1,995
g), corn starch (350 g) and crystalline cellulose (350 g) were
charged in a fluidized bed granulating dryer (Flow coater FLO-5,
manufactured by FREUND INDUSTRIAL CO., LTD.), and these granulating
ingredients were mixed by fluidizing for about 3 minutes with an
inlet air temperature at 70.degree. C. and air flow rate of 3
m.sup.3/min. Further, the granulating ingredients were upon
continued fluidizing under the same condition and sprayed about
1,400 g of the aqueous solution to obtained wet granules. The wet
granules were dried under inlet air at temperature at 80.degree.
C., for about 15 minutes. The obtained dried granules contained
4.3% of water. (Yield: 99%). The dried granules were subjected to
sizing by passing to a sieve of 710 .mu.m.
About 1% by weight of magnesium stearate was added to the sized
granules and mixed, then the granules were supplied to a tablet
machine (Rotary single tablet press 12HUK: manufactured by KIKUSUI
SEISAKUSHO CO., LTD.), there were obtained tablets, each having 95
mg of weight.
Water content of the tablets was measured according to volumetric
titration method (Karl-Fischer method) described in water content
measuring method in Japanese Pharmacopoea or the electrical
quantity titration method.
Water Content Measuring Method:
Sample (0.1 to 0.5 g) (in case of a tablet, 1 tablet was used) was
weighed precisely, and the water content was measured by use of a
water content measuring equipment.
Volumetric titration: Automated water content measuring equipment
Model: KF-06 (manufacture by MITSUBISHI CHEMICAL CORP.)
Electrical quantity titration method: Automated micro-water content
measuring equipment Model: AQ-7F (manufactured by HIRANUMA SANGYO
CO., LTD.) Automated water vaporization equipment Model: LE-20S
(manufactured by HIRANUMA SANGYO CO., LTD.) Heating temperature:
165.+-.10.degree. C. Nitrogen gas flow rate: about 150 ml/min.
Reference Example 5
Preparation of 15 mg tablets containing type B crystals of
anhydrous aripiprazole
Type B crystals of anhydrous aripiprazole (4,500 g), lactose
(17,100 g), corn starch (3,000 g) and crystalline cellulose (3,000
g) were charged in a fluidized bed granulating dryer
(NEW-MARUMERIZER Model: NQ-500, manufactured by FUJI PAUDAL CO.,
LTD.), and these granulating ingredients were mixed by fluidizing
for about 3 minutes with an inlet air temperature at 70.degree. C.,
air flow rate of 10 to 15 m.sup.3/min. Further, the granulating
ingredients were upon continued fluidizing under the same
condition, and sprayed about 12,000 g of 5% aqueous solution of
hydroxypropyl celulose to obtained wet granules. The wet granules
were dried under inlet air at temperature at 85.degree. C., for
about 28 minutes. The thus obtained dried granules contained 3.8%
of water (measured by the method according to Reference Example 4).
(Yield: 96%). The dried granules were subjected to sizing by
passing to a sieve of 850 .mu.m.
About 1% by weight of magnesium stearate was added to the sized
granules and mixed, then the granules were supplied to a tablet
machine (Rotary single tablet press 12HUK: manufactured by KIKUSUI
SEISAKUSHO CO., LTD.), there were obtained tablets, each having 95
mg of weight.
Example 1
500.3 g of the aripiprazole hydrate crystals obtained in Reference
Example 3 were milled using a sample mill (small atomizer). The
main axis rotation rate was set to 12,000 rpm and the feed rotation
rate to 17 rpm, and a 1.0 mm herringbone screen was used. Milling
was completed in 3 minutes, resulting in 474.6 g (94.9%) of
Aripiprazole Hydrate A powder.
The Aripiprazole Hydrate A (powder) obtained in this way had a mean
particle size of 20-25 .mu.m. The melting point (mp) was
undetermined because dehydration was observed beginning near
70.degree. C.
The Aripiprazole Hydrate A (powder) obtained above exhibited an
.sup.1H-NMR (DMSO-d.sub.6, TMS) spectrum which was substantially
the same as the .sup.1H-NMR spectrum shown in FIG. 2. Specifically,
it had characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm
(m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78
ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t,
J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz,
J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H),
7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).
The Aripiprazole Hydrate A (powder) obtained above had a powder
x-ray diffraction spectrum which was substantially the same as the
powder x-ray diffraction spectrum shown in FIG. 3. Specifically, it
had characteristic peaks at 2.theta.=12.6.degree., 15.4.degree.,
17.3.degree., 18.0.degree., 18.6.degree., 22.5.degree. and
24.8.degree.. This pattern is different from the powder x-ray
spectrum of unmilled aripiprazole hydrate shown in FIG. 7.
The Aripiprazole Hydrate A (powder) obtained above had infrared
absorption bands at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963
and 784 cm.sup.-1 on the IR (KBr) spectrum.
As shown in FIG. 1, the Aripiprazole Hydrate A (powder) obtained
above had a weak peak at 71.3.degree. C. in
thermogravimetric/differential thermal analysis and a broad
endothermic peak (weight loss observed corresponding to one water
molecule) between 60-120.degree. C.--clearly different from the
endothermic curve of unmilled aripiprazole hydrate (see FIG.
6).
Example 2
450 g of the Aripiprazole Hydrate A (powder) obtained in Example 1
was dried for 24 hours at 100.degree. C. using a hot air dryer to
produce 427 g (yield 98.7%) of Anhydrous Aripiprazole Crystals
B.
These Anhydrous Aripiprazole Crystals B had a melting point (mp) of
139.7.degree. C.
The Anhydrous Aripiprazole Crystals B obtained above had an
.sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was substantially
the same as the .sup.1H-NMR spectrum shown in FIG. 4. Specifically,
they had characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78
ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO),
2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm
(t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4
Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m,
1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).
The Anhydrous Aripiprazole Crystals B obtained above had a powder
x-ray diffraction spectrum which was substantially the same as the
powder x-ray diffraction spectrum shown in FIG. 5. Specifically,
they had characteristic peaks at 2.theta.=11.0.degree.,
16.6.degree., 19.3.degree., 20.3.degree. and 22.1.degree..
The Anhydrous Aripiprazole Crystals B obtained above had remarkable
infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377,
1173, 960 and 779 cm.sup.-1 on the IR (KBr) spectrum.
The Anhydrous Aripiprazole Crystals B obtained above exhibited an
endothermic peak near about 141.5.degree. C. in
thermogravimetric/differential thermal analysis.
The Anhydrous Aripiprazole Crystals B obtained above exhibited an
endothermic peak near about 140.7.degree. C. in differential
scanning calorimetry.
Even when the Anhydrous Aripiprazole Crystals B obtained above were
left for 24 hours in a dessicator set at humidity 100%, temperature
60.degree. C., they did not exhibit hygroscopicity exceeding 0.4%
(See Table 1 below).
Example 3
44.29 kg of the Aripiprazole Hydrate A (powder) obtained in Example
1 was dry heated for 18 hours in a 100.degree. C. hot air dryer and
then heated for 3 hours at 120.degree. C. to produce 42.46 kg
(yield 99.3%) of Anhydrous Aripiprazole Crystals B.
The physicochemical properties of the resulting Anhydrous
Aripiprazole Crystals B were the same as the physicochemical
properties of the Anhydrous Aripiprazole Crystals B obtained in
Example 2.
The Anhydrous Aripiprazole Crystals B obtained in this way did not
exhibit hygroscopicity of more than 0.4% even when left for 24
hours in a dessicator set at humidity 100%, temperature 60.degree.
C. (see Table 1 below).
Example 4
40.67 kg of the Aripiprazole Hydrate A (powder) obtained in Example
1 was dry heated for 18 hours in a 100.degree. C. hot air dryer and
then heated for 3 hours at 120.degree. C. to produce 38.95 kg
(yield 99.6%) of Anhydrous Aripiprazole Crystals B.
The physicochemical properties of the resulting Anhydrous
Aripiprazole Crystals B were the same as the physicochemical
properties of the Anhydrous Aripiprazole Crystals B obtained in
Example 2.
The Anhydrous Aripiprazole Crystals B obtained in this way did not
exhibit hygroscopicity of more than 0.4% even when left for 24
hours in a dessicator set at humidity 100%, temperature 60.degree.
C. (see Table 1 below).
Examples 5-10 are useful for injectable or oral solution
formulations but not solid dose formulations since they were made
by heating Conventional Anhydrous Aripiprazole or Conventional
Hydrate instead of Hydrate A.
Example 5
The hygroscopic anhydrous aripiprazole crystals obtained in
Reference Example 1 were heated for 50 hours at 100.degree. C.
using the same methods as in Example 2. The physicochemical
properties of the resulting Anhydrous Aripiprazole Crystals B were
the same as the physicochemical properties of the Anhydrous
Aripiprazole Crystals B obtained in Example 2.
The Anhydrous Aripiprazole Crystals B obtained in this way did not
exhibit hygroscopicity of more than 0.4% even when left for 24
hours in a dessicator set at humidity 100%, temperature 60.degree.
C. (see Table 1 below).
Example 6
The hygroscopic anhydrous aripiprazole crystals obtained in
Reference Example 1 were heated for 3 hours at 120.degree. C. using
the same methods as in Example 2. The physicochemical properties of
the resulting Anhydrous Aripiprazole Crystals B were the same as
the physicochemical properties of the Anhydrous Aripiprazole
Crystals B obtained in Example 2.
The Anhydrous Aripiprazole Crystals B obtained in this way did not
exhibit hygroscopicity of more than 0.4% even when left for 24
hours in a dessicator set at humidity 100%, temperature 60.degree.
C. (see Table 1 below).
Example 7
The hygroscopic anhydrous aripiprazole crystals obtained in
Reference Example 2 were heated for 50 hours at 100.degree. C.
using the same methods as in Example 2. The physicochemical
properties of the resulting Anhydrous Aripiprazole Crystals B were
the same as the physicochemical properties of the Anhydrous
Aripiprazole Crystals B obtained in Example 2.
The Anhydrous Aripiprazole Crystals B obtained in this way did not
exhibit hygroscopicity of more than 0.4% even when left for 24
hours in a dessicator set at humidity 100%, temperature 60.degree.
C. (see Table 1 below).
Example 8
The hygroscopic anhydrous aripiprazole crystals obtained in
Reference Example 2 were heated for 3 hours at 120.degree. C. using
the same methods as in Example 2. The physicochemical properties of
the resulting Anhydrous Aripiprazole Crystals B were the same as
the physicochemical properties of the Anhydrous Aripiprazole
Crystals B obtained in Example 2.
The Anhydrous Aripiprazole Crystals B obtained in this way did not
exhibit hygroscopicity of more than 0.4% even when left for 24
hours in a dessicator set at humidity 100%, temperature 60.degree.
C. (see Table 1 below).
Example 9
The aripiprazole hydrate crystals obtained in Reference Example 3
were heated for 50 hours at 100.degree. C. using the same methods
as in Example 2. The physicochemical properties of the resulting
Anhydrous Aripiprazole Crystals B were the same as the
physicochemical properties of the Anhydrous Aripiprazole Crystals B
obtained in Example 2.
The Anhydrous Aripiprazole Crystals B obtained in this way did not
exhibit hygroscopicity of more than 0.4% even when left for 24
hours in a dessicator set at humidity 100%, temperature 60.degree.
C. (see Table 1 below).
Example 10
The aripiprazole hydrate crystals obtained in Reference Example 3
were heated for 3 hours at 120.degree. C. using the same methods as
in Example 2. The physicochemical properties of the resulting
Anhydrous Aripiprazole Crystals B were the same as the
physicochemical properties of the Anhydrous Aripiprazole Crystals B
obtained in Example 2.
The Anhydrous Aripiprazole Crystals B obtained in this way
exhibited hygroscopicity of no more than 0.4% even when left for 24
hours in a dessicator set at humidity 100%, temperature 60.degree.
C. (see Table 1 below).
Example 11
Preparation of Type C Crystals of Anhydrous Aripiprazole
100 Milligrams of type-I crystals of anhydrous aripiprazole
obtained in Reference Example 2 were heated about 145.degree. C.
(.+-.3.degree. C.). In this occasion, there was observed the
phenomena that the crystals were once melted, then again
crystallized. After that, 100 mg (yield: 100%) of Type C crystals
of anhydrous aripiprazole were obtained. The melting point of the
crystals was 150.degree. C. The crystals were colorless prism
form.
The type C crystals of anhydrous aripiprazole obtained above had an
endothermic curve which was substantially identical to the
endothermic curve of thermogravimetric/differential thermal
analysis (heating rate: 5.degree. C./minute) shown in FIG. 8.
Specifically, it showed the endothermic curve around 150.2.degree.
C.
The type C crystals of anhydrous aripiprazole thus obtained
exhibited an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was
substantially identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6,
TMS) shown in FIG. 9. Specifically, it had the characteristic peaks
at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m,
4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97
ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d,
J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d,
J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H), and
10.00 ppm (s, 1H).
The type C crystals of anhydrous aripiprazole obtained above had a
powder X-ray diffraction spectrum which was substantially identical
to the powder X-ray diffraction spectrum shown in FIG. 10.
Specifically, it had the characteristic peaks at
2.theta.=12.6.degree., 13.7.degree., 15.4.degree., 18.1.degree.,
19.0.degree., 20.6.degree., 23.5.degree. and 26.4.degree..
The type C crystals of anhydrous aripiprazole obtained above had an
IR spectrum which was substantially identical to the IR (KBr)
spectrum shown in FIG. 11. Specifically, it had the characteristic
infrared absorption bands at 2939, 2804, 1680, 1375 and 780
cm.sup.-1.
The type C crystals of anhydrous aripiprazole obtained above
exhibited a solid .sup.13C-NMR spectrum, which was substantially
identical to the solid .sup.13C-NMR spectrum shown in FIG. 12.
Specifically, it had the characteristic peaks at 32.8 ppm, 60.8
ppm, 74.9 ppm, 104.9 ppm, 152.2 ppm, 159.9 ppm and 175.2 ppm.
According to the above-mentioned data on endothermic curve of
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) and powder X-ray diffraction spectrum, the
formation of the type C crystals of anhydrous aripiprazole was
confirmed.
When the type C crystals of anhydrous aripiprazole crystals
obtained above were left for 24 hours in a dessicator where the
conditions were set at humidity 100%, and temperature 60.degree.
C., then the crystals did not exhibit hygroscopicity higher than
0.4% (see, Table 1 below).
Example 12
Preparation of Type D Crystals of Anhydrous Aripiprazole)
The type-I crystals of anhydrous aripiprazole obtained in Reference
Example 2 were added in 200 ml of toluene, and dissolved by heating
at 74.degree. C. After confirmed that it was dissolved completely,
the toluene solution was cooled to 7.degree. C., and the
precipitated crystals were collected by filtration. The crystals
were subjected to air-drying as they were so as to obtain 17.9 g
(yield: 89.5%) of type D crystals of anhydrous aripiprazole.
The type D crystals of anhydrous aripiprazole obtained above had an
endothermic curve substantially identical to the endothermic curve
of thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) shown in FIG. 13. Specifically, it had the
endothermic peaks at about 136.8.degree. C. and about
141.6.degree..
The type D crystals of anhydrous aripiprazole obtained above
exhibited .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was
substantially identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6,
TMS) shown in FIG. 14. Specifically, they had the characteristic
peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46
ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz,
2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43
ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04
ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m,
2H), and 10.00 ppm (s, 1H).
The type D crystals of anhydrous aripiprazole obtained above had a
powder X-ray diffraction spectrum which was substantially identical
to the powder X-ray diffraction spectrum shown in FIG. 15.
Specifically, it had the characteristic peaks at
2.theta.=8.7.degree., 11.6.degree., 16.3.degree., 17.7.degree.,
18.6.degree., 20.3.degree., 23.4.degree. and 25.0.degree..
The type D crystals of anhydrous aripiprazole obtained above had an
IR spectrum which was substantially identical to the IR (KBr)
spectrum shown in FIG. 16. Specifically, it had the characteristic
infrared absorption bands at 2946, 1681, 1375, 1273, 1175 and 862
cm.sup.-1.
The type D crystals of anhydrous aripiprazole obtained above
exhibited a solid .sup.13C-NMR spectrum which was substantially
identical to the solid .sup.13C-NMR spectrum shown in FIG. 17.
Specifically, it had the characteristic peaks at 32.1 ppm, 62.2
ppm, 66.6 ppm, 104.1 ppm, 152.4 ppm, 158.5 ppm and 174.1 ppm.
According to the above-mentioned data on the endothermic curve of
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) and powder X-ray diffraction spectrum, the
formation of type D crystals of anhydrous aripiprazole was
confirmed.
When the type D crystals of anhydrous aripiprazole crystals
obtained above were left for 24 hours in a dessicator where the
conditions were set at humidity 100%, and temperature 60.degree.
C., the crystals did not have hygroscopicity higher than 0.4% (see,
Table 1 below).
Example 13
Preparation of Type D Crystals of Anhydrous Aripiprazole
1,200 Grams of the type-I crystals of anhydrous aripiprazole
obtained in Reference Example 2 were dissolved in 18 liters of
toluene, with heating. This toluene solution was cooled to
40.degree. C., and 36 g of type-D crystals of anhydrous
aripiprazole obtained in Example 12 were added as seed crystals,
then the solution was cooled to 10.degree. C. and allowed to stand
as it is. The precipitated crystals were collected by filtration,
dried at 60.degree. C. for 18 hours to obtain 1,073 g (yield:
86.8%) of type D crystals of anhydrous aripiprazole (purity: 100%).
The crystals were colorless plate form.
The type D crystals of anhydrous aripiprazole had an endothermic
curve substantially identical to the endothermic curve of
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) shown in FIG. 13. Specifically, it had the
endothermic peaks around about 136.8.degree. C. and about
141.6.degree..
The type D crystals of anhydrous aripiprazole obtained above
exhibited an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was
substantially identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6,
TMS) shown in FIG. 14. Specifically, it had the characteristic
peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46
ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz,
2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43
ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04
ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m,
2H), and 10.00 ppm (s, 1H).
The type D crystals of anhydrous aripiprazole obtained above had a
powder X-ray diffraction spectrum which was substantially identical
to the powder X-ray diffraction spectrum shown in FIG. 15.
Specifically, it had the characteristic peaks at
2.theta.=8.7.degree., 11.6.degree., 16.3.degree., 17.7.degree.,
18.6.degree., 20.3.degree., 23.4.degree. and 25.0.degree..
The type D crystals of anhydrous aripiprazole obtained above had an
IR spectrum which was substantially identical to the IR (KBr)
spectrum shown in FIG. 16. Specifically, it had characteristic
infrared absorption bands at 2946, 1681, 1375, 1273, 1175 and 862
cm.sup.-1.
The type D crystals of anhydrous aripiprazole obtained above had a
solid .sup.13C-NMR spectrum which was substantially identical to
the solid .sup.13C-NMR spectrum shown in FIG. 17. Specifically, it
had the characteristic peaks at 32.1 ppm, 62.2 ppm, 66.6 ppm, 104.1
ppm, 152.4 ppm, 158.5 ppm and 174.1 ppm.
According to the above-mentioned data on the endothermic curve of
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) and powder X-ray diffraction spectrum, the
formation of type D crystals of anhydrous aripiprazole was
confirmed.
When the type D crystals of anhydrous aripiprazole crystals
obtained above were left for 24 hours in a dessicator where the
conditions were set at humidity 100%, and temperature 60.degree.
C., the crystals did not exhibit hygroscopicity higher than 0.4%
(see, Table 1 below).
Example 14
Preparation of Type E Crystals of Anhydrous Aripiprazole
40 Grams of type-I crystals of anhydrous aripiprazole obtained in
Reference Example 2 was dissolved in 1000 ml of acetonitrile with
heating at 80.degree. C. This acetonitrile solution was cooled to
about 70.degree. C. by taking for about 10 minutes, and was kept at
this temperature for about 30 minutes to precipitate the seed
crystals. Next, the temperature of said solution was slowly risen
to 75.degree. C., and the crystals were grown up by keeping this
temperature for 1 hour. Then, the solution was cooled to 10.degree.
C. by taking about 4 hours, and the precipitated crystals were
collected by filtration. Thus obtained crystals were subjected to
air-drying overnight, there were obtained 37.28 g (yield: 93.2%) of
type E crystals of anhydrous aripiprazole (purity: 100%). The
melting point of these crystals was 145.degree. C., and the
crystals were colorless needle form.
The type E crystals of anhydrous aripiprazole had an endothermic
curve substantially identical to the endothermic curve of
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) shown in FIG. 18. Specifically, it had
endothermic peak at about 146.5.degree..
The type E crystals of anhydrous aripiprazole obtained above
exhibited an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was
substantially identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6,
TMS) shown in FIG. 19. Specifically, it had the characteristic
peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46
ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz,
2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43
ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04
ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m,
2H), and 10.00 ppm (s, 1H).
The type E crystals of anhydrous aripiprazole obtained above had a
powder X-ray diffraction spectrum which was substantially identical
to the powder X-ray diffraction spectrum shown in FIG. 20.
Specifically, it had the characteristic peaks at
2.theta.=8.0.degree., 13.7.degree., 14.6.degree., 17.6.degree.,
22.5.degree. and 24.0.degree..
The type E crystals of anhydrous aripiprazole obtained above had an
IR spectrum which was substantially identical to the IR (KBr)
spectrum shown in FIG. 21. Specifically, it had the characteristic
infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969 and
774 cm.sup.-1.
According to the data on the endothermic curve of
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) and powder X-ray diffraction spectrum, the
formation of type E crystals of anhydrous aripiprazole was
confirmed.
When the type E crystals of anhydrous aripiprazole obtained above
were left for 24 hours in a dessicator where the conditions were
set at humidity 100%, and temperature 60.degree. C., the crystals
did not exhibit hygroscopicity higher than 0.4% (see, Table 1
below).
Example 15
Preparation of Type F Crystals of Anhydrous Aripiprazole
140 Grams of type-I crystals of anhydrous aripiprazole obtained in
Reference Example 2 were suspended in 980 ml of acetone and
continued to reflux for 7.5 hours with stirring. Next, the
suspension was filtered in hot condition, and crystals separated
out were subjected to air-drying for 16 hours at room temperature,
there was obtained 86.19 g (yield: 61.6%) of type F crystals of
anhydrous aripiprazole (purity: 100%). The crystals were colorless
prism form.
The type F crystals of anhydrous aripiprazole had an endothermic
curve substantially identical to the endothermic curve of
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) shown in FIG. 22. Specifically, it had the
exothermic peaks at about 137.5.degree. C. and about 149.8.degree.
C.
The type F crystals of anhydrous aripiprazole obtained above
exhibited an .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) which was
substantially identical to the .sup.1H-NMR spectrum (DMSO-d.sub.6,
TMS) shown in FIG. 23. Specifically, it had the characteristic
peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46
ppm (m, 4H), 2.48-2.56 ppm (m, 4H+DMSO), 2.78 ppm (t, J=7.4 Hz,
2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43
ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04
ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m,
2H), and 10.00 ppm (s, 1H).
The type F crystals of anhydrous aripiprazole obtained above had a
powder X-ray diffraction spectrum which was substantially identical
to the powder X-ray diffraction spectrum shown in FIG. 24.
Specifically, it had the characteristic peaks at
2.theta.=11.3.degree., 13.3.degree., 15.4.degree., 22.8.degree.,
25.2.degree. and 26.9.degree..
The type F crystals of anhydrous aripiprazole obtained above had an
IR spectrum which was substantially identical to the IR (KBr)
spectrum shown in FIG. 25. Specifically, it had the characteristic
infrared absorption bands at 2940, 2815, 1679, 1383, 1273, 1177,
1035, 963 and 790 cm.sup.-1
According to the data on endothermic curve of
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./minute) and powder X-ray diffraction spectrum, the
formation of type F crystals of anhydrous aripiprazole was
confirmed.
When the type F crystals of anhydrous aripiprazole crystals
obtained above were left for 24 hours in a dessicator where the
conditions were set at humidity 100%, and temperature 60.degree.
C., the crystals did not exhibit hygroscopicity higher than 0.4%
(see, Table 1 below).
TABLE-US-00001 TABLE 1 Initial Moisture Moisture Content Sample
Content (%) After 24 hrs (%) Reference Example 1 0.04 3.28
Reference Example 2 0.04 1.78 Example 2 0.04 0.04 Example 3 0.02
0.02 Example 4 0.02 0.02 Example 5 0.04 0.04 Example 6 0.04 0.04
Example 7 0.04 0.03 Example 8 0.04 0.03 Example 9 0.03 0.01 Example
10 0.05 0.05 Example 11 0.03 0.03 Example 12 0.04 0.03 Example 13
0.04 0.03 Example 14 0.06 0.09 Example 15 0.04 0.04
Example 16
a) Type I crystals of anhydrous aripiprazole (10 g) obtained in
Reference Example 2 was charged in a stainless steel round tray
(diameter: 80 mm), and heated to about 170.degree. C. so as to
melted completely. When this melted liquid was cooled, then it
solidified clarity with pale brawn in color, the solid was peeled
off from the stainless steel round tray, there was obtained 9.8 g
(yield: 98%) of glassy state of anhydrous aripiprazole. The
obtained glassy state product was characterized by having no
significant peak observed in a powder X-ray determination. (cf.
FIG. 31).
According to the thermogravimetric/differential thermal analysis
(heating rate: 5.degree. C./minute), as shown in FIG. 30, an
exothermic peak of type B crystals of anhydrous aripiprazole was
observed at around 86.5.degree. C. While, an endothermic peak of
type B crystals of anhydrous aripiprazole owing to melting was
observed at around 140.1.degree. C.
b) When the glassy state of anhydrous aripiprazole obtained in
Example 16-a) were charged in a sealed vessel and left to stand at
room temperature for about 6 months, then type G crystals of
anhydrous aripiprazole having white in color was obtained by
changing the color from pale brown (25 g, yield: 100%). Melting
point: 138 to 139.degree. C.
The type G crystals of anhydrous aripiprazole had an endothermic
curve which was substantially identical to the
thermogravimetric/differential thermal analysis (heating rate:
5.degree. C./min.) endothermic curve shown in FIG. 26, more
particularly, it has an endothermic peak around 141.0.degree. C.
and an exothermic peak around 122.7.degree. C.
The type G crystals of anhydrous aripiprazole obtained as above
exhibited an .sup.1H-NMR spectrum which was substantially identical
to the .sup.1H-NMR spectrum (DMSO-d.sub.6, TMS) shown in FIG. 27.
Specifically, it has characteristic peaks at 1.55-1.63 ppm (m, 2H),
1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m,
4H+DMSO), 2.78 ppm (t, J=7.4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H),
3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm
(dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17
ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).
The type G crystals of anhydrous aripiprazole obtained as above had
a powder X-ray diffraction spectrum which was substantially
identical to the powder X-ray diffraction spectrum shown in FIG.
28. Specifically, it has characteristic peak at
2.theta.=10.1.degree., 12.8.degree., 15.2.degree., 17.0.degree.,
17.5.degree., 19.1.degree., 20.1.degree., 21.2.degree.,
22.4.degree., 23.3.degree., 24.5.degree. and 25.8.degree..
The type G crystals of anhydrous aripiprazole obtained above had an
IR spectrum which was substantially identical to the IR (KBr)
spectrum shown in FIG. 29. Specifically, it has clear infrared
absorption bands at 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787
cm.sup.-1.
Example 17
a) Preparation of granules of 30 mg tablets containing type B
crystals of anhydrous aripiprazole for additional drying
Type B crystals of anhydrous aripiprazole (1,500 g), lactose (5,700
g), corn starch (1,000 g) and crystalline cellulose (1,000 g) were
charged in a fluidized bed granulating dryer (Flow Coater Model
FLO-5M; manufactured by FROINT SANGYO KABUSHIKI KAISHA), and these
granulating ingredients were mixed by fluidizing for about 3
minutes with an inlet air temperature at 60.degree. C., air flow
rate of 3 to 4 m.sup.3/min. Further, the granulating ingredients
were continued fluidizing under the same condition, and sprayed
with about 4,000 g of 5% aqueous solution of hydroxypropyl celulose
to obtain wet granules. The wet granules were dried under an inlet
air temperature at 85.degree. C., for about 20 minutes. The
obtained dried granules contained 3.8% of water (measured by the
method according to Reference Example 4).
b) The dried granules (4 kg) obtained in Example 17-a) were sized
by use of a mill (FIORE F-0: manufactured by TOKUJU
CORPORATION).
The sized granules (3 kg) were charged in a fluidized bed
granulating dryer (Flow Coater Model FLO-5M; manufactured by FREUND
INDUSTRIAL CO., LTD.), and these granulating ingredients were dried
under an inlet air temperature at 85.degree. C., and air flow rate
of 2 m.sup.3/min for 2 hours. The obtained dried granules contained
3.6% of water (measured by the method according to Reference
Example 4).
About 1% by weight of magnesium stearate was added to the sized
granules and mixed, then the granules were supplied to a tabletting
machine (a Rotary single tablet press, Model VIRGO: manufactured by
KIKUSUI SEISAKUSHO CO., LTD.), and there were obtained tablets,
each having 190 mg of weight.
c) The dried granules (3 kg) obtained in Example 17-a) were charged
in a vacuum dryer (vacuum granulating dryer model; VG-50:
manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and dried at
70.degree. C. of a jacket temperature, under a reduced pressure at
5 torr of degree of vacuum for 1 hour. The thus obtained dried
granules contained 3.1% of water (measured by the method according
to Reference Example 4). The dried granules were subjected to
sizing by passing to a sieve of 850 .mu.m.
About 1% by weight of magnesium stearate was added to the sized
granules and mixed, then the granules were supplied to a tablet
machine (Rotary single tablet press, Model VIRGO: manufactured by
KIKUSUI SEISAKUSHO CO., LTD.), and there were obtained tablets,
each having 190 mg of weight.
Example 18
a) Preparation of 30 Mg Tablets Containing Type B Crystals of
Anhydrous Aripiprazole
Anhydrous aripiprazole (type B crystals) (4,500 g), lactose (17,100
g), corn starch (3,000 g) and crystalline cellulose (3,000 g) were
charged in a fluidized bed granulating dryer (NEW-MARUMERIZER
Model: NQ-500, manufactured by FUJI PAUDAL CO., LTD.), and these
granulating ingredients were mixed by fluidizing for about 3
minutes with an inlet air temperature at 70.degree. C., air flow
rate of 10-15 m.sup.3/min. Further, the granulating ingredients
were continued fluidizing under the same condition, and were
sprayed with about 12,000 g of 5% aqueous solution of hydroxypropyl
celulose to obtain wet granules. The wet granules were dried under
inlet air at temperature of 85.degree. C., for about 30 minutes.
The obtained dried granules contained 3.6% of water (measured by
the method according to Reference Example 4). (Yield: 96%). The
dried granules were sized by passing to a mill (FIOLE F-0:
manufactured by TOKUJU CORPORATION).
About 1% by weight of magnesium stearate was added to the sized
granules and mixed, then the granules were supplied to a tablet
machine (a Rotary single tablet press, VIRGO: manufactured by
KIKUSUI SEISAKUSHO CO., LTD.), and there were obtained tablets,
each having 190 mg of weight.
b) The tablets (5 kg) obtained in Example 18-a) were charged in a
fan dryer (AQUA COATER AQC-48T, manufactured by FREUND INDUSTRIAL
CO., LTD.), and dried under inlet air at temperature of 90.degree.
C., air flow rate of 2 m.sup.3/min for 6 hours. The obtained dried
granules contained 3.3% of water (measured by the method according
to Reference Example 4). c) The dried tablets (3 kg) obtained in
Example 18-a) were charged in a vacuum dryer (vacuum granulating
dryer, VG-50: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and
dried at 80.degree. C. of a jacket temperature, under reduced
pressure of 5 torr of degree of vacuum for 4 hours. The obtained
dried tablets contained 2.7% of water (measured by the method
according to Reference Example 4).
Example 19
a) By the procedures similar to those of Example 18-a), there were
obtained tablets (containing type I crystals of anhydrous
aripiprazole obtained in Reference Example 2), each having 190 mg
of weight,
b) The tablets were dried by the procedures similar to those of
Example 18-b), except that air inlet temperature was 100.degree. C.
and dried for 1 hour.
c) The tablets were dried by the procedures similar to those of
Example 18-b), except that inlet air temperature was 100.degree. C.
and dried for 3 hours.
Example 20
By the procedures similar to those of Example 18-a), there were
obtained tablets, each having 190 mg of weight, containing type C
crystals of anhydrous aripiprazole.
Example 21
By the procedures similar to those of Example 18-a), there were
obtained tablets, each having 190 mg of weight, containing type D
crystals of anhydrous aripiprazole.
Example 22
a) Aripiprazole hydrate crystals (156 g) obtained in Reference
Example 3, lactose (570 g), corn starch (100 g) and crystalline
cellulose (100 g) were charged in a fluidized bed granulating dryer
(NEW-MARUMERIZER, NQ-160: manufactured by FUJI POWDAL CO., LTD.),
and these granulating ingredients were mixed under fluidizing for
about 3 minutes with an inlet air temperature at 60.degree. C., air
flow rate of 1.0 to 1.5 m.sup.3/min, and rotating disc with rotary
speed of 400 rpm. Further, the granulating ingredients were
continued fluidizing under the same condition, and sprayed about
500 g of 4% aqueous solution of hydroxypropyl celulose to obtain
wet granules. The inlet air temperature was elevated up to
85.degree. C., and dried until the temperature of the product was
reached to 46.degree. C. The obtained dried granules were sized by
passing to a sieve of 850 .mu.m. The dried granules contained 4.37%
of water (measured by the method according to Reference Example
4).
b) The dried granules (200 g) obtained in Example 22-a) were
charged in a fluidized bed dryer (multiplex, MP-01: manufactured by
POWREX CORPORATION), and dried at 85.degree. C. of inlet air
temperature, air flow rate of 0.5 m.sup.3/min for 2 hours. The
dried granules contained 3.50% of water (measured by the method
according to Reference Example 4). c) The dried granules (100 g)
obtained in Example 22-a) were charged in a vacuum dryer (vacuum
granulating dryer LCV-232: manufactured by TABAI CO., LTD.), and
dried 80.degree. C. of tray temperature, about 760 mmHg of degree
of vacuum for 2 hours. The dried granules were further dried
similarly for 6 hours. The dried granules contained 3.17% of water
(the product being dried for 2 hours: measured by the method
according to Reference Example 4). The further dried granules
contained 2.88% of water (the product being dried for 6 hours:
measured by the method according to Reference Example 4). d) About
1% by weight of magnesium stearate was added to the sized granules
being obtained in Example 22-b) and mixed, then the mixed granules
were supplied to a tablet machine (Single type Tablet machine No.
2B: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), and tabletted
with punch, there were obtained tablets, each having 191 mg of
weight. e) About 1% by weight of magnesium stearate was added to
the sized granules being obtained in Example 22-c) and mixed, then
the mixed granules were supplied to a tablet machine (Single type
Tablet machine No. 2B: manufactured by KIKUSUI SEISAKUSHO CO.,
LTD.), and tabletted with punch, there were obtained tablets, each
having 191 mg of weight. Dissolution Test
Each tablets of the pharmaceutical solid oral preparations obtained
previously was kept, respectively under the open at 25.degree.
C./60% RH for 6 months, and at 40.degree. C./75% RH for 1 week,
then their dissolution rates were measured by the following
methods. The dissolution rates obtained from 60 minutes after the
exposure are shown in Tables 2 and 3. The dissolution rates after
60 minutes, using the tablets kept under the open at 40.degree.
C./75% RH for 2 weeks, are shown in Tables 4 and 5. The dissolution
rates after 60 minutes, using the tablets kept under the open
condition at 40.degree. C./75% RH for 1 week, are shown in Table 6.
Dissolution test equipment: USP Model: NTR-6100 (manufactured by
TOYAMA SANGYO CO., LTD.) Model: DT-610 (manufactured by JASCO
CORPORATION) a) Method of Dissolution Test of the 15 Mg Tablet
One tablet (containing 15 mg each of anhydrous aripiprazole or
hydrate) was tested by using 900 ml of acetic acid buffer solution
(pH 5.0) (Note: 1) as the test solution, and by rotating a paddle
at 100 rpm according to the method of USP (United States
Pharmacopoea) (Note: 2).
The test solutions obtained respectively from 10 minutes, 20
minutes, 30 minutes, 45 minutes and 60 minutes after the start of
test are named as T10, T20, T30, T45 and T60.
On the other hand, about 0.05 g of standard sample of aripiprazole
was weighed accurately, dissolved in ethanol (95%) so as to make
exactly 50 ml of ethanol solution. Twenty (20) ml of this ethanol
solution was taken accurately, and to prepared exactly 1000 ml of
the standard solution by adding 0.01 mol/liter of hydrochloric acid
reagent solution (Note: 3).
The test solutions and the standard solution were subjected to
filtration, respectively by using a filter having micropores of 10
to 20 .mu.m in diameters, then each of the filtrates were
introduced to a spectrophotometer installed with flow cell (cell
length: 10 mm), and to measure the absorbance of wave length at 249
nm and absorbance of wave length at 325 nm and determined the
differences between absorbances to named as At10, At20, At30, At45,
At60 and As, respectively.
After the measurements, the test solutions of T10, T20, T30 and T45
were put back to the test vessels respectively. Further, similar
procedures were conducted to other 5 samples of the test solutions.
Dissolution rate(%) relating to the indicated amount of
aripiprazole=Amount of the standard sample of
aripiprazole(mg).times.At.times.As.times.9/5.times.20/C
wherein,
At: At10, At20, At30, At45 or At60
As: standard solution
C: Indicated amount of aripiprazole (mg) (Note:1) Water was added
to 1.97 g of acetic acid (100) and 9.15 g of sodium
acetate.trihydrate to make 1000 ml of solution (0.1 mol/l).
(Note:2) Paddle method (Note:3) Water was added to 100 ml of 0.1
mol/l hydrochloric acid (Note:4) to make 1000 ml of solution.
(Note:4) Water was added to 0.9 ml of hydrochloric acid to make
1000 ml of solution. b) Method of Dissolution Test of the 30 Mg
Tablet
One tablet each of the pharmaceutical solid oral preparations
(containing 30 mg each of anhydrous aripiprazole or hydrate) was
tested by using 900 ml of acetic acid buffer solution (pH 4.5)
(Note: 5) as the test solution, and to conduct the test by rotating
a paddle at 75 rpm in accordance with the method of USP (United
States Pharmacopoea) (Note: 6).
The test solutions obtained respectively from 10 minutes, 20
minutes, 30 minutes 45 minutes and 60 minutes after the start of
test, were named as T10, T20, T30, T45 and T60.
On the other hand, about 0.05 g of the standard sample of
aripiprazole was weighed accurately, and dissolved in ethanol (95%)
so as to made exactly 50 ml of the ethanol solution. Twenty (20) ml
of the ethanol solution was taken accurately, and prepared exactly
1000 ml of the standard solution by adding 0.01 mol/liter of
hydrochloric acid reagent solution (Note: 7).
The test solutions and standard solution were subjected to
filtration, respectively by using a filter having micropores of 10
to 20 .mu.m in diameters, then each of the filtrates were
introduced to a spectrophotometer in which a flow cell (cell
length: 10 mm) was installed, and measured the absorbance of wave
length at 249 nm and absorbance of wave length at 325 nm, and the
difference between these absorbances were named as At10, At20,
At30, At45, At60 and As, respectively.
After the measurements, the test solutions of T10, T20, T30 and T45
were put back respectively to the test vessels. Further, similar
procedures were conducted to other 5 samples of the test solutions.
Dissolution rate(%)relating to the indicated amount of
aripiprazole=Amount of the standard sample of
aripiprazole(mg).times.At.times.As.times.9/5.times.20/C
wherein,
At: At10, At20, At30, At45 or At60
As: standard solution
C: Indicated amount of aripiprazole (mg) (Note:5) Water was added
to 1.91 g of acetic acid (100) and 2.99 g of sodium
acetate.trihydrate to made 1000 ml of solution (0.05 mol/l).
(Note:6) Paddle method (Note:7) Water is added to 100 ml of 0.1
mol/l hydrochloric acid (Note:8) to made 1000 ml of solution.
(Note:8) Water was added to 0.9 ml of hydrochloric acid to make
1000 ml of solution.
TABLE-US-00002 TABLE 2 Open at 25.degree. C./ Open at 40.degree.
C./ 60% RH 75% RH After After Samples used Initial 6 months Initial
1 week Tablet (15 mg) 83.4% 44.3% 83.4% 44.1% of Reference Example
4 Tablet (15 mg) 90.1% 61.9% 90.1% 65.2% of Reference Example 5
TABLE-US-00003 TABLE 3 Open at 25.degree. C./ Open at 40.degree.
C./ 60% RH 75% RH After After Samples used Initial 6 months Initial
1 week Tablet (30 mg) 96.7% 77.1% 96.7% 75.9% of Example 18-a)
Tablet (30 mg) 96.5% 93.6% 95.0% 92.2% of Example 17-b) Tablet (30
mg) 97.0% 96.3% 94.7% 94.8% of Example 17-c) Tablet (30 mg) 97.2%
95.3% 97.2% 97.8% of Reference Example 18-b) Tablet (30 mg) 97.8%
96.3% 97.8% 96.9% of Reference Example 18-c)
TABLE-US-00004 TABLE 4 Samples used Initial After 2 weeks Samples
used Tablet 89.8% 66.9% (30 mg) of Example 19-a) Tablet (30 mg) of
-- 79.8% Example 19-b) Tablet (30 mg) of -- 85.9% Example 19-c)
TABLE-US-00005 TABLE 5 Samples used Initial After 2 weeks Tablet
(30 of 94.8% 94.7% Example 18-a) Tablet (30 mg) of 93.7% 93.1%
Example 20 Tablet (30 mg) of 94.8% 90.9% Example 21
TABLE-US-00006 TABLE 6 Samples used Initial After 1 weeks Tablet
(30 mg) of 96.5% 84.5% Example 22-d) Tablet (30 mg) of 92.5% 74.4%
Example 22-e) (dreid for 2 hours) Tablet (30 mg) of 96.2% 83.4%
Example 22-e) (dreid for 6 hours) (Note: Dissolution tests in Table
5 were conducted similarly to the procedures in the above-mentioned
"b) Method of dissolution test of the 30 mg tablet" except that by
using 900 ml of acetic acid buffer solution (pH 4.0) as the test
solution, and by rotating a paddle at 50 rpm.
As can be seen clearly from the data shown in Table 2, in
comparison with the 15 mg tablet containing conventional anhydrous
aripiprazole crystals (Reference Example 4), the 15 mg tablet
containing type B crystals of anhydrous aripiprazole (Reference
Example 5) had the dissolution rate to maintain maximum drug
concentration (Cmax), at pH 5.0 after 60 minutes, even though such
tablet was kept under the open at 25.degree. C./60% RH for 6 months
and under the open at 40.degree. C./75% RH for 1 week.
As can be seen clearly from the data shown in Table 3, even though
30 mg tablets (Examples 17-b) and 17-c)) prepared from twice dried
granules of type B crystals of anhydrous aripiprazole, and 30 mg
tablets (Examples 18-b) and 18-c)) prepared from further dried
pharmaceutical solid oral preparation containing type B crystals of
anhydrous aripiprazole were subjected to keep under the open at
25.degree. C./60% RH for 6 months or 40.degree. C./75% RH for 1
week, the dissolution rates of these tablets obtained 60 minutes
after the test at pH 4.5 were not substantially lowered.
As can be seen clearly from the data shown in Table 4, when 30 mg
tablets (Examples 19-a), 19-b) and 19-c)) containing conventional
anhydrous aripiprazole crystals were further dried and subjected to
keep under open at 40.degree. C./75% RH for 2 weeks, then the
dissolution rates of the tablets obtained 60 minutes after the test
at pH 4.5 were the dissolution rates to maintain maximum drug
concentration (Cmax).
As can be seen clearly from the data shown in Table 5, when 30 mg
tablet (Example 18-a)) containing type B crystals of anhydrous
aripiprazole, 30 mg tablet (Example 20) containing type C crystals
of anhydrous aripiprazole and 30 mg tablet (Example 21) containing
type D crystals of anhydrous aripiprazole were subjected to keep
under open at 40.degree. C./75% RH for 2 weeks, then the
dissolution rates of the tablets obtained 60 minutes after the test
at pH 4.0 were not substantially lowered.
As can be seen clearly from the data shown in Table 6, when 30 mg
tablets (Examples 22-d) and 22-e)) prepared from granules of
conventional aripiprazole hydrate being twice dried, and subjected
to keep under open at 40.degree. C./75% RH for 1 week, then the
dissolution rates of the tablets obtained 60 minutes after the test
at pH 4.5 were the dissolution rates to maintain maximum drug
concentration (Cmax).
Sample Preparation 1
TABLE-US-00007 Anhydrous aripiprazole crystals B 5 mg Starch 131 mg
Magnesium stearate 4 mg Lactose 60 mg Total 200 mg
Tablets containing the above ingredients in each tablet were
prepared by formulation methods known to one skilled in the art of
pharmaceutical formulation.
Sample Preparation 2
TABLE-US-00008 Type C crystals of anhydrous aripiprazole 5 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200
mg
In accordance with an ordinary method, tablet preparation,
containing the above-mentioned ingredients per 1 tablet was
prepared.
Sample Preparation 3
TABLE-US-00009 Type D crystals of anhydrous aripiprazole 5 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200
mg
In accordance with an ordinary method, tablet preparation,
containing the above-mentioned ingredients per 1 tablet was
prepared.
Sample Preparation 4
TABLE-US-00010 Type E crystals of anhydrous aripiprazole 5 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200
mg
In accordance with an ordinary method, tablet preparation,
containing the above-mentioned ingredients per 1 tablet was
prepared.
Sample Preparation 5
TABLE-US-00011 Type F crystals of anhydrous aripiprazole 5 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200
mg
In accordance with an ordinary method, tablet preparation,
containing the above-mentioned ingredients per 1 tablet was
prepared.
Sample Preparation 6
TABLE-US-00012 Type G crystals of anhydrous aripiprazole 5 mg
Starch 131 mg Magnesium stearate 4 mg Lactose 60 mg Total 200
mg
In accordance with an ordinary method, tablet preparation,
containing the above-mentioned ingredients per 1 tablet was
prepared.
Formulation Example
The following examples used aripiprazole drug substance made by
first milling or pulverizing the conventional hydrate of
aripiprazole and then heating it to form the anhydrous form
(anhydrous aripiprazole crystals B).
Formulation Example 1
Flash-melt tablets were prepared as follows:
Intragranulation:
TABLE-US-00013 Mg. per Ingredient Percent w/w tablet Xylitol (300)
Xylisorb 26 52 Avicel .RTM. PH 102 12 24 Calcium Silicate 43.35
86.7 Crospovidone 3 6 Amorphous silica 2 4 Aspartame 2 4 Wild
cherry flavor 0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4 Magnesium
stearate 0.25 0.5 Total weight 92.75 185.5
The ingredients except for the magnesium stearate were blended in a
commercial V-blender in geometric proportions for 5 minutes each
until all were added. The magnesium stearate was then added and the
mixture blended for an additional three minutes. The blended
formulation was compacted at a pressure of 30-35 kgF/cm.sup.2 in a
commercial compactor equipped with an orifice such that the
compacts therefrom are in the form of ribbons. The ribbons were
passed through a 30 mesh (600 microns) screen to form stable
granules of about 150 to 400 microns.
Extragranulation Ingredients:
TABLE-US-00014 Mg. per Ingredient Percent w/w tablet
Intragranulation 92.75 185.5 Avicel .RTM. PH 200 3 6 Crospovidone 4
8 Magnesium stearate 0.25 0.5 Total weight 100 200
The intragranulation was placed in the blender and the Avicel.RTM.
PH 200 and crospovidone added thereto and blended for five minutes.
The magnesium stearate was then added and the mixture blended for
an additional three minutes to form the final blend. Tablets
compressed therefrom had a breaking force of 2.3 kP (3.5 SCU) and
disintegrated in 10 seconds in 5 ml of water. The final blend
formulation demonstrated excellent flow and was free of other
problems such as chipping, capping and sticking. It has been found
that utilizing Avicel.RTM. PH 102 for the intragranulation and
Avicel.RTM. PH 200 for the extragranulation ingredient enhanced the
quality of the resultant tablets.
Formulation Example 2
Flash-melt tablets containing a combination of two grades of
calcium silicate were prepared as follows:
Intragranulation:
TABLE-US-00015 Mg. per Ingredient Percent w/w tablet Xylitol (300)
Xylisorb 26 52 Avicel .RTM. PH 102 12 24 Calcium Silicate 33.35
66.7 (crystalline, alpha triclinic) Hubersorb 600 NF 10 20
(amorphous calcium silicate) Crospovidone 3 6 Amorphous silica 2 4
Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4
Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Total weight 92.75
185.5
The ingredients except for the magnesium stearate were blended in a
commercial V-blender in geometric proportions for 5 minutes each
until all were added. The magnesium stearate was added and the
mixture blended for an additional three minutes. The blended
formulation was compacted, and screened to form stable granules in
accordance with the procedure of Formulation Example 1.
Extragranulation Ingredients:
TABLE-US-00016 Mg. per Ingredient Percent w/w tablet
Intragranulation 92.75 185.5 Avicel .RTM. PH 200 3 6 Crospovidone 4
8 Magnesium stearate 0.25 0.5 Total weight 100 200
The intragranulation was placed in the blender and the Avicel.RTM.
PH 200 and crospovidone added thereto and blended for five minutes.
The magnesium stearate was then added and the mixture blended for
an additional three minutes to form the final blend. Tablets
compressed therefrom had a breaking force of 2.0 kP (3.1 SCU) and
disintegrated in 10 seconds in 5 ml of water.
Formulation Example 3
Flash-melt tablets containing aripiprazole, an antischizophrenic
drug, were prepared as follows:
Intragranulation
TABLE-US-00017 Mg. per Ingredient Percent w/w tablet Aripiprazole
15 30 Xylitol (300) Xylisorb 25 50 Avicel .RTM. PH 102 6 12 Calcium
Silicate 37 74 Crospovidone 3 6 Amorphous silica 2 4 Aspartame 2 4
Wild cherry flavor 0.15 0.3 Tartaric acid 2 4 Acesulfame K 2 4
Magnesium stearate 0.25 0.5 Total weight 94.4 188.8
The ingredients except for the magnesium stearate were blended in a
commercial V-blender in geometric proportions for 5 minutes each
until all were added. The magnesium stearate was added and the
mixture blended for an additional three minutes. The blended
formulation was compacted, and screened to form stable granules in
accordance with the procedure of Formulation Example 1.
Extragranulation Ingredients:
TABLE-US-00018 Mg. per Ingredient Percent w/w tablet
Intragranulation 94.4 188.8 Avicel .RTM. PH 200 1.1 2.2
Crospovidone 4 8 Magnesium stearate 0.5 1 Total weight 100 200
The intragranulation was placed in the blender and the Avicel.RTM.
PH 200 and crospovidone added thereto and blended for five minutes.
The magnesium stearate was then added and the mixture blended for
an additional three minutes to form the final blend. Tablets
compressed therefrom had a breaking force of 2.0 kP (3.1 SCU) and
disintegrated in 10 seconds in 5 ml of water.
Formulation Example 4
Flash-melt tablets containing aripiprazole were prepared as
follows:
Intragranulation:
TABLE-US-00019 Mg. per Ingredient Percent w/w tablet Aripiprazole
0.5 1 Xylitol (300) Xylisorb 27 54 Avicel .RTM. PH 102 12 24
Calcium Silicate 42 84 Crospovidone 3 6 Amorphous silica 2 4
Aspartame 2 4 Wild cherry flavor 0.15 0.3 Tartaric acid 2 4
Acesulfame K 2 4 Magnesium stearate 0.25 0.5 Total weight 92.9
185.8
The ingredients except for the magnesium stearate were blended in a
commercial V-blender in geometric proportions for 5 minutes each
until all were added. The magnesium stearate was added and the
mixture blended for an additional three minutes. The blended
formulation was compacted, and screened to form stable granules in
accordance with the procedure of Formulation Example 1.
Extragranulation Ingredients:
TABLE-US-00020 Mg. per Ingredient Percent w/w tablet
Intragranulation 92.9 185.8 Avicel .RTM. PH 200 2.6 5.2
Crospovidone 4 8 Magnesium stearate 0.5 1 Total weight 100 200
The intragranulation was placed in the blender and the Avicel.RTM.
PH 200 and crospovidone added thereto and blended for five minutes.
The magnesium stearate was then added and the mixture blended for
an additional three minutes to form the final blend. Tablets
compressed therefrom had a breaking force of 2.3 kP (3.5 SCU) and
disintegrated in 10 seconds in 5 ml of water.
* * * * *
References